Submissions for variant NM_000179.3(MSH6):c.1870G>A (p.Gly624Ser)

gnomAD frequency: 0.00003  dbSNP: rs868760377

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219912	SCV000274550	likely benign	Hereditary cancer-predisposing syndrome	2018-08-16	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.
Invitae	RCV000233003	SCV000283735	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000657004	SCV000566081	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Maxwell et al., 2015; Bradbury et al., 2018); This variant is associated with the following publications: (PMID: 21097718, 23621914, 30212499, 31762146, 25503501, 32095738, 21120944, 17531815, 24608573)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484834	SCV000601521	uncertain significance	not specified	2017-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219912	SCV000690230	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 624 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 breast cancer (PMID: 25503501, 32095738). This variant has been identified in 3/281786 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.
Counsyl	RCV000662524	SCV000785082	uncertain significance	Lynch syndrome 5	2017-05-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000484834	SCV001338333	uncertain significance	not specified	2022-03-29	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1870G>A (p.Gly624Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250392 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1870G>A has been reported in the literature in individuals affected with breast cancer (example, Maxwell_2014, Bradbury_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, five classified as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000662524	SCV004018466	uncertain significance	Lynch syndrome 5	2023-03-27	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.
Baylor Genetics	RCV003469017	SCV004195722	uncertain significance	Endometrial carcinoma	2023-06-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997865	SCV004835478	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 624 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 breast cancer (PMID: 25503501, 32095738). This variant has been identified in 3/281786 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.