Submissions for variant NM_000179.3(MSH6):c.3832C>A (p.Pro1278Thr)

gnomAD frequency: 0.00002  dbSNP: rs587782109

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130625	SCV000185501	likely benign	Hereditary cancer-predisposing syndrome	2020-02-07	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	RCV001086478	SCV000218656	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000589175	SCV000279324	uncertain significance	not provided	2023-02-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast, prostate, or colorectal cancer (Tung et al., 2015; Abe et al., 2019; Dharwadkar et al., 2020); This variant is associated with the following publications: (PMID: 30883245, 31391288, 25186627, 33359728, 17531815, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV000130625	SCV000685448	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 1278 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 31391288, 33359728), an individual not affected with cancer who has a family history of various cancers (PMID: 30883245). This variant also has been reported in three individuals affected with breast and/or ovarian cancer, in which two carriers also have a pathogenic CHEK2 covariant (PMID: 25186627). This variant has been identified in 26/250902 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260255	SCV000695891	likely benign	not specified	2020-09-16	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3832C>A (p.Pro1278Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250902 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3832C>A has been reported in the literature in individuals affected with cancer including breast and ovarian cancer (e.g. Tung 2015, Li_2020) but it was also reported in an individual with no personal history of cancer who was above the average age of onset for Hereditary Nonpolyposis Colorectal Cancer (Abe_2019). Co-occurrences with pathogenic variants have been reported in the literature in individuals affected with breast and ovarian cancer (BRCA1 c.3759_3760delTA, p.Lys1254GlufsX12; CHEK2 c.1283C>T, p.Ser428Phe) (Tung_2015) and also via internal testing (MSH6 c.2150_2153delTCAG, p.V717fsX18), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589175	SCV001469827	uncertain significance	not provided	2019-09-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130625	SCV002528075	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-22	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000589175	SCV004224914	uncertain significance	not provided	2022-07-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998071	SCV004835149	uncertain significance	Lynch syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 1278 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 31391288, 33359728), an individual not affected with cancer who has a family history of various cancers (PMID: 30883245). This variant also has been reported in three individuals affected with breast and/or ovarian cancer, in which two carriers also have a pathogenic CHEK2 covariant (PMID: 25186627). This variant has been identified in 26/250902 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.