Submissions for variant NM_000179.3(MSH6):c.2147C>T (p.Thr716Ile)

gnomAD frequency: 0.00001  dbSNP: rs587782805

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132365	SCV000187455	likely benign	Hereditary cancer-predisposing syndrome	2019-03-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000212659	SCV000211292	uncertain significance	not provided	2021-03-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast or pancreatic cancer (Tung 2015, Shindo 2017, Hu 2020); This variant is associated with the following publications: (PMID: 28767289, 25186627, 32659497)
Counsyl	RCV000411918	SCV000488260	uncertain significance	Lynch syndrome 5	2016-02-12	criteria provided, single submitter	clinical testing
Invitae	RCV000468830	SCV000551149	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132365	SCV000690245	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 716 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pancreatic cancer (PMID: 28767289, 32659497) and breast cancer (PMID: 25186627). This variant has been identified in 1/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000411918	SCV004019058	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003998145	SCV004836041	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 716 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pancreatic cancer (PMID: 28767289, 32659497) and breast cancer (PMID: 25186627). This variant has been identified in 1/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.