Submissions for variant NM_000179.3(MSH6):c.3079G>C (p.Val1027Leu)

dbSNP: rs876658397

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216842	SCV000273550	likely benign	Hereditary cancer-predisposing syndrome	2018-05-24	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	RCV001080207	SCV000283782	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000227272	SCV001134420	uncertain significance	not provided	2018-08-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216842	SCV001359122	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 1027 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 an individual affected with pancreatic cancer (PMID: 25479140). This variant has not been identified 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.
GeneDx	RCV000227272	SCV003852970	uncertain significance	not provided	2023-03-27	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 an individual with pancreatic cancer (Grant et al., 2015); This variant is associated with the following publications: (PMID: 17531815, 21120944, 34944796, 25479140)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330587	SCV004038738	uncertain significance	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3079G>C (p.Val1027Leu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245130 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3079G>C has been reported in the literature in individuals affected with breast cancer or pancreatic cancer without strong evidence of causality (Tung_2014, Grant_2015). 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. The following publications have been ascertained in the context of this evaluation (PMID: 25186627, 25479140, 34944796). Five submitters have cited clinical-significance assessment for this variant to ClinVar after 2014, and classified it as uncertain significance (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997803	SCV004837091	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 1027 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 an individual affected with pancreatic cancer (PMID: 25479140). This variant has not been identified 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503628	SCV000592621	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Val1027Leu variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project, Exome Aggregation Consortium (March 14, 2016), COSMIC, ClinVar, Clinvitae, GeneInsight COGR, MutDB, Mismatch Repair Genes Variant, MMR Gene Unclassified Variants, UMD Colon Cancer, InSIGHT Colon Cancer or Zhejiang Databases. The variant was identified on the LOVD-MSH6 variant database classified as “Unknown”. The p.Val1027 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The c.3079G>C variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.