Submissions for variant NM_000179.3(MSH6):c.643G>A (p.Val215Ile)

gnomAD frequency: 0.00006  dbSNP: rs145959653

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197162	SCV000254332	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220344	SCV000276053	likely benign	Hereditary cancer-predisposing syndrome	2023-12-29	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.
Counsyl	RCV000663025	SCV000786051	uncertain significance	Lynch syndrome 5	2018-02-16	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761118	SCV000891034	uncertain significance	Lynch syndrome	2020-10-15	criteria provided, single submitter	clinical testing	The MSH6 c.643G>A (p.Val215Ile) missense change has a maximal subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48025765-G-A). Five of six in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in an individual with colorectal adenoma (PMID: 29245953). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Color Diagnostics, LLC DBA Color Health	RCV000220344	SCV000903133	likely benign	Hereditary cancer-predisposing syndrome	2016-01-07	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000663025	SCV002032302	uncertain significance	Lynch syndrome 5	2021-12-01	criteria provided, single submitter	clinical testing	The MSH6 c.643G>A (p.Val215Ile) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48025765-G-A?dataset=gnomad_r2_1). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported as somatic in individuals with adenocarcinoma (PMID: 33294277), colorectal adenoma (PMID: 29245953) and endometrial cancer (PMID: 23104009). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001699153	SCV002046791	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with endometrial cancer (PMID: 23104009 (2012)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00025 (5/19862 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000220344	SCV002536338	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	curation
GeneDx	RCV001699153	SCV003803536	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a microsatellite stable serous endometrial tumor, as well as both cases and controls in a breast cancer study (Le Gallo et al., 2012; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33294277, 21437237, 23104009, 23621914, 33471991, 37226842)
Myriad Genetics, Inc.	RCV000663025	SCV004018892	likely benign	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV003468905	SCV004197625	uncertain significance	Endometrial carcinoma	2023-10-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000582427	SCV000691918	uncertain significance	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699153	SCV001925195	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001699153	SCV001927329	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001699153	SCV001954585	likely benign	not provided		no assertion criteria provided	clinical testing