Submissions for variant NM_000179.3(MSH6):c.3758T>C (p.Val1253Ala)

dbSNP: rs202066386

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656902	SCV000211326	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25559809, 24728327, 30122538, 25980754, 29360161, 17531815, 21120944)
Ambry Genetics	RCV000160698	SCV000214443	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-24	criteria provided, single submitter	clinical testing	The p.V1253A variant (also known as c.3758T>C), located in coding exon 8 of the MSH6 gene, results from a T to C substitution at nucleotide position 3758. The valine at codon 1253 is replaced by alanine, an amino acid with similar properties. This variant was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This variant was identified in an individual with colon cancer the was microsatellite stable who had a family history of colon cancer in two relatives (Chubb D et al. J. Clin. Oncol., 2015 Feb;33:426-32). This variant was also detected in a patient with a personal history of pancreatic and ovarian cancer but was also positive for a mutation in the BRCA1 gene, and there was no family history of Lynch syndrome related cancers (Dudley B et al. Cancer, 2018 04;124:1691-1700). This variant has been identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE, 2014 Apr;9:e94554). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000206271	SCV000260238	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000411602	SCV000489110	uncertain significance	Lynch syndrome 5	2016-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160698	SCV000690394	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 1253 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 colon cancer (PMID: 25559809), Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), and ovarian and pancreatic cancer (PMID: 29360161). This variant has been identified in 5/282588 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	RCV000121589	SCV000917739	uncertain significance	not specified	2023-05-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3758T>C (p.Val1253Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251190 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3758T>C has been reported in the literature in individuals affected with Colorectal Cancer, Hereditary Breast Cancer, or suspected Lynch syndrome without evidence for causality, often reported as a VUS (Chubb_2015, Yurgelun_2015, Dudley_2018, Pearlman_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 25559809, 29360161, 34250417). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as uncertain significance (n=7) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656902	SCV001713989	uncertain significance	not provided	2019-05-28	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000656902	SCV002503065	uncertain significance	not provided	2021-12-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411602	SCV004018980	likely benign	Lynch syndrome 5	2023-03-29	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	RCV003460856	SCV004197676	uncertain significance	Endometrial carcinoma	2023-10-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656902	SCV004222014	uncertain significance	not provided	2022-05-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000039 (5/128956 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hereditary breast and ovarian cancer (PMID: 29360161 (2018)), colorectal cancer (PMID: 25559809 (2015)), and in unaffected control individuals (PMIDs: 24728327 (2014)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMIDs: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997354	SCV004835130	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 1253 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 colon cancer (PMID: 25559809), Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), and ovarian and pancreatic cancer (PMID: 29360161). This variant has been identified in 5/282588 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.
ITMI	RCV000121589	SCV000085785	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000160698	SCV000788053	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing