Submissions for variant NM_000179.3(MSH6):c.1526T>C (p.Val509Ala)

gnomAD frequency: 0.00067  dbSNP: rs63751005

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074661	SCV000107863	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1% in a specific population
GeneDx	RCV000034492	SCV000149285	benign	not provided	2018-11-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24055113, 25637381, 15184898, 24978188, 16341805, 22703879, 22949387, 23621914, 20176959, 16237223, 27153395, 25985138, 28531214, 14520694)
Invitae	RCV001079926	SCV000166211	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115376	SCV000184181	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Pathway Genomics	RCV000172817	SCV000223783	likely benign	Lynch syndrome 1	2014-10-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000178051	SCV000230037	likely benign	not specified	2015-03-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115376	SCV000537406	likely benign	Hereditary cancer-predisposing syndrome	2014-12-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000178051	SCV000539704	uncertain significance	not specified	2017-01-10	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been classified as Likely benign in ClinVar with 3 stars by InSiGHT (expert panel), Pathway Genomics, Emory, CSER_CC_NCGL, and as Benign by Invitae, GeneDx, Ambry, and as VUS by Mayo and Biesecker lab. It has been seen in 9 papers in HGMD, with the comments mostly suggesting that it is likely benign. It is in gnomAD at a frequency of 2.3% of Ashkenazi Jewish chromosomes.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659890	SCV000781787	uncertain significance	Lynch syndrome 5	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034492	SCV000885718	likely benign	not provided	2018-05-06	criteria provided, single submitter	clinical testing	The MSH6 c.1526T>C; p.Val509Ala variant (rs63751005) is reported in the literature in individuals with lynch syndrome (Hegde 2005, Lipkin 2004), but is also found in the general population with an overall allele frequency of 0.1% (268/276940 alleles, including 2 homozygotes) in the Genome Aggregation Database, with an increased frequency of 2.3% in the Askenazi Jewish population. Functional analyses do not show a significant impact on protein function (Houlleberghs 2017, Martinez 2010). This variant is reported as benign or likely benign by multiple laboratories in ClinVar (Variation ID: 41588). The valine at codon 509 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the high frequency in the general population, this variant is considered to be likely benign. REFERENCES Hegde M et al. Assay validation for identification of hereditary nonpolyposis colon cancer-causing mutations in mismatch repair genes MLH1, MSH2, and MSH6. J Mol Diagn. 2005 Oct;7(4):525-34. Houlleberghs H et al. Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity. PLoS Genet. 2017 May 22;13(5):e1006765. Lipkin SM et al. The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nat Genet. 2004 Jul;36(7):694-9. Martinez SL et al. Functional analysis of human mismatch repair gene mutations identifies weak alleles and polymorphisms capable of polygenic interactions. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5070-5.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034492	SCV000888243	benign	not provided	2022-08-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000659890	SCV001135807	benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000659890	SCV001299859	uncertain significance	Lynch syndrome 5	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000034492	SCV001502308	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MSH6: BS1
Genetic Services Laboratory, University of Chicago	RCV000178051	SCV002066162	benign	not specified	2021-05-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115376	SCV002535634	benign	Hereditary cancer-predisposing syndrome	2020-09-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000178051	SCV002552295	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477055	SCV002800647	likely benign	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149603	SCV003838318	benign	Breast and/or ovarian cancer	2022-01-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541067	SCV004764129	benign	MSH6-related disorder	2019-04-30	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034492	SCV000043355	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000074661	SCV000190358	likely benign	Lynch syndrome	2016-08-15	no assertion criteria provided	research	Originally interpreted based on literature review PMID: 25637381. Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 63 year male with a history of over 30 colon polyps and a family history of colon cancer.
Mayo Clinic Laboratories, Mayo Clinic	RCV000178051	SCV000257214	uncertain significance	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354372	SCV001548974	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Val509Ala variant was identified in 4 of 344 proband chromosomes (frequency: 0.01) from individuals or families with hereditary non-polyposis colon cancer and was present in 4 of 1512 control chromosomes (frequency: 0.003) from healthy individuals (Dovrat 2005, Hedge 2005, Peterlongo 2003, Johnston 2012). The variant was also identified in dbSNP (rs63751005) as “with other allele”, ClinVar (classified as likely benign by InSiGHT expert panel in 2013, Color, Eurofins and 4 other submitters; as benign by Invitae, GeneDx, Ambry Genetics and 1 other submitter; and as uncertain significance by Mayo Clinic and 3 other submitters) and UMD-LSDB (observed 5x). The variant was identified in control databases in 278 of 282,624 chromosomes (3 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 244 of 10,364 chromosomes (freq: 0.02), Other in 13 of 7218 chromosomes (freq: 0.002), and European in 21 of 129,016 chromosomes (freq: 0.0002), while it was not observed in the African, Latino, East Asian, Finnish or South Asian populations. The variant had no observed effect on MMR activity in mouse embryonic stem cells (Houlleberghs 2017). The p.Val509 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000178051	SCV001808421	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034492	SCV001921261	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034492	SCV001959706	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115376	SCV002050290	benign	Hereditary cancer-predisposing syndrome	2021-12-17	no assertion criteria provided	clinical testing