Submissions for variant NM_000179.3(MSH6):c.2827G>T (p.Asp943Tyr)

gnomAD frequency: 0.00001  dbSNP: rs143520357

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131640	SCV000186664	likely benign	Hereditary cancer-predisposing syndrome	2019-08-15	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.
GeneDx	RCV000212672	SCV000211303	uncertain significance	not provided	2023-10-16	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, colorectal, and/or pancreatic cancer (PMID: 25479140, 25186627, 34326862, Walker et al. 2023. https://www.mdpi.com/2072-6694/15/20/4925); This variant is associated with the following publications: (PMID: 23621914, 25186627, 25479140, 17531815, 21120944, 34326862, Walker2023[article])
Invitae	RCV000205918	SCV000261184	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000412088	SCV000489142	uncertain significance	Lynch syndrome 5	2016-08-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131640	SCV000537570	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 943 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 an individual affected with pancreatic cancer (PMID: 25479140) and at least 5 individuals affected with breast cancer (PMID: 25186627, 33471991). This variant has been identified in 13/281888 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.
Myriad Genetics, Inc.	RCV000412088	SCV004019039	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].
All of Us Research Program, National Institutes of Health	RCV001356309	SCV004836343	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 943 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 an individual affected with pancreatic cancer (PMID: 25479140) and at least 5 individuals affected with breast cancer (PMID: 25186627, 33471991, LOVD variant #0000747836). This variant has been identified in 13/281888 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356309	SCV001551439	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Asp943Tyr variant was identified in 1 of 580 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic cancer (Grant_2015_25479140). A bioinformatics tool, CoDP (Combination of the Different Properties) integrating the prediction results of three methods (MAPP, PolyPhen-2 and SIFT) and two structural properties, found the variant impacted the MSH6 protein (Terui_2013_23621914). The variant was also identified in dbSNP (ID: rs143520357) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics), Clinvitae (4x), and in control databases in 13 of 276196 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). It was identified in the European Non-Finnish population in 13 of 125940 chromosomes (freq: 0.0001); and was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish and South Asian populations. The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database or the Insight Hereditary Tumors Database. The p.Asp943 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.