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Endometrial/uterine cancers or tumours – referring to genetics

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Referral to a clinical genetics service or familial cancer centre opens in a new tab or window for assessment should be considered for all people meeting the categories below:

Pathogenic variant identified in the family
UNTESTED adult blood relative of a person with an identified germline pathogenic variant in an endometrial cancer or uterine tumour predisposition gene (e.g. MLH1, MSH2, MSH6, FH, PMS2, POLE, POLD1, PTEN).
Blood relative of a person with a clinical diagnosis of a familial cancer syndrome that predisposes to endometrial cancer or uterine tumours (e.g. Lynch syndrome, PTEN hamartoma syndrome, hereditary leiomyomatosis and renal cell carcinoma [HLRCC])
Tumour pathology 
Characteristics that warrant referral irrespective of other factors
Endometrial cancer that is MMR-deficient (except where there is loss of expression of MLH1, and hypermethylation of the MLH1 promoter is present)
Uterine leiomyoma with atypical histopathology and FH deficiency on immunohistochemistry

Rare endometrial tumours e.g. uterine sarcoma, uterine papillary serous carcinoma

An individual with endometrial cancer in whom tumour testing has identified a somatic BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, POLE, POLD1 or PTEN pathogenic variant with a variant allele frequency (VAF) greater than 30%*
For those with a personal history of endometrial cancer
Individual characteristics that warrant referral irrespective of other factors
Endometrial cancer diagnosed under age 45 years

Endometrial cancer AND one of the following:

  • personal history of a second Lynch syndrome-associated cancer#
  • one close relative** with colorectal or endometrial cancer diagnosed under age 50 years
  • two or more close relatives** with a Lynch syndrome-associated cancer#

Endometrial cancer and features of PTEN hamartoma/Cowden syndrome, including but not limited to:

  • macrocephaly
  • hamartomatous colorectal polyps 
  • multiple oral mucosal papillomas 
  • multiple cutaneous trichilemmoma 
  • thyroid cancer (non-medullary)

Uterine leiomyoma and features of hereditary leiomyomatosis and renal cell carcinoma (HLRCC):

  • renal cell carcinoma (RCC) with histopathology consistent with HLRCC*** and/or FH deficient on immunohistochemistry OR
  • multiple cutaneous leiomyomas (at least one histopathologically confirmed) OR
  • uterine leiomyoma with atypical FH-associated pathology and/or which is FH deficient on immunohistochemistry OR

An individual with two or more of the following:

  • a single cutaneous leiomyoma (histopathologically confirmed)
  • multiple symptomatic uterine leiomyomas
  • RCC with HLRCC-associated pathology (expert pathology review may be required)***
  • a first-degree relative with a clinical feature of HLRCC
For those with a family history of cancer
Characteristics sufficient to warrant referral irrespective of other factors
Close relative** with endometrial cancer and one or more Lynch syndrome-associated cancer(s)#, regardless of the age the cancers were diagnosed
Two or more close relatives** with endometrial or colorectal cancer, with at least one of the cancers diagnosed under age 50 years
Three or more close relatives** with a Lynch syndrome-associated cancer#, regardless of the age the cancers were diagnosed
Family history of endometrial cancer and/or features of PTEN hamartoma/Cowden syndrome (see above)

Family history of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) 

*VAF of 30% or greater for single nucleotide variants (SNVs) and 20% or greater for small insertions and deletions is the recommended threshold for suspecting a variant may be germline
** Close relative = 1st or 2nd degree
***HLRCC-associated RCCs are predominantly high-grade with a papillary growth pattern. However, HLRCC-associated RCCs have been described to show tubulopapillary, tubulocystic, tubular, solid and cystic areas and may overlap morphologically with collecting duct carcinomas. Multiple architectural patterns, including sarcomatoid and rhabdoid components, may be seen within the same tumour. Large nuclei with prominent orangiophilic or eosinophilic nucleolus surrounded by a clear halo are often observed.rr
# Lynch syndrome-associated cancer includes adenocarcinoma of the colorectum, endometrium, small intestine, stomach, ovary, or pancreas, urothelial carcinoma of the ureter or renal pelvis, cholangiocarcinoma, brain tumour, sebaceous gland tumour

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Version 7

Date Summary of changes
11/12/2024

Document reviewed out of session by cancer genetics reference committee. Approved for publication with the following changes made:

  • Title updated
  • Pathogenic variant identified in the family:
    • Row 1: FH, POLE, POLD1 added
  • Tumour pathology:
    • Row 2, 3 and 4 added to table
  • For those with a personal history of endometrial cancer:
    • Uterine leiomyoma and features of hereditary leiomyomatosis and renal cell carcinoma added
  • For those with a family history of cancer:
    • Family history of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) added
  • Other minor wording changes made throughout the document

Version number increased to V.7. Approved on 9/12/2024, published on 11/12/2024. Review in 2 years. 

Version 6

Date Summary of changes
23/01/2023

First sentence updated to align with the new eviQ cancer genetics referral guidelines template:

  • Changed from "All of the people who fall into the categories below warrant a referral to a clinical genetics service or familial cancer centre for assessment." to "Referral to a clinical genetics service or familial cancer centre for assessment should be considered for all people meeting the categories below".

Version number increased to V.6.

Version 5

Date Summary of changes
23/12/2021

Document reviewed out of session by cancer genetics reference committee. Approved for publication with the following changes made:

  • For those with a personal history of endometrial cancer:
    • Row 4: added link to 'PTEN hamartoma tumour syndrome clinical diagnostic criteria'
  • For those with a family history of cancer:
    • Row 2: added to table
    • Row 5: added to table 
  • Other minor wording changes made throughout the document

Version number increased to V.5. Review in 2 years. Approved on 23/12/2021, published on 10/01/2022.

Version 4

Date Summary of changes
17/11/2020

Document updated with the following changes made in accordance with cancer genetics reference committee chairs consensus:

  • Document title changed from "Referral guidelines for endometrial cancer risk assessment and consideration of genetic testing" to "Endometrial cancer – referring to genetics"
  • First table heading changed to "Pathogenic variant identified in the family" 

Version number increased to V.4.

Version 3

Date Summary of changes
10/09/2019

Referral guidelines reviewed at May 2019 reference committee meeting. Approved for publication with the following changes made:

  • Blood relative of a person with a clinical diagnosis of a familial cancer syndrome that predisposes to endometrial cancer (e.g.Lynch syndrome or PTEN hamartoma syndrome) - added 
  • Tumour pathology - sarcoma of the endometrium (e.g. leiomyosarcoma) <60 years - removed
  • For those with a personal history of endometrial cancer - referral criteria reviewed and updated. "Endometrial carcinoma diagnosed under the age of 50 years" changed to "Endometrial cancer under the age of 45 years."
  • For those with a family history of cancer - referral criteria reviewed updated
  • "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up.

Protocol version number increased to V.3. To be reviewed in 2 years.

Version 2

Date Summary of changes
28/07/2016 Referral guidelines template updated and protocol approved via email.  Previously this protocol (ID 1953) was part of ID 1134 Ovarian and endometrial cancer referral guidelines.
24/08/2016 'Endometrium' added to Lynch syndrome associated cancers list.  
31/05/2017 Transferred to new eviQ website. Version number changed to V.2.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1953

20 May 2025