Submissions for variant NM_000179.3(MSH6):c.1471ATG[1] (p.Met492del)

dbSNP: rs587782576

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131804	SCV000186857	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-10	criteria provided, single submitter	clinical testing	The c.1474_1476delATG variant (also known as p.M492del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame ATG deletion at nucleotide positions 1474 to 1476. This results in the in-frame deletion of a methionine at codon 492. This alteration 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 also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome and was diagnosed with breast cancer at age 55 (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000417386	SCV000211384	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Located in the critical mismatch binding domain (Warren et al., 2007; Kansikas et al., 2011); Identified in individuals with Lynch-related cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 17531815, 21120944, 25980754)
Invitae	RCV000225825	SCV000283716	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-14	criteria provided, single submitter	clinical testing	This variant, c.1474_1476del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Met492del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs745312505, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 21520333, 25980754). ClinVar contains an entry for this variant (Variation ID: 142597). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000131804	SCV000685195	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of a single amino acid of the MSH6 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in an individual affected with breast cancer (PMID: 32885271). This variant has been identified in 1/251194 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.
Baylor Genetics	RCV003462024	SCV004197737	uncertain significance	Endometrial carcinoma	2023-09-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544300	SCV004789048	uncertain significance	MSH6-related disorder	2023-11-02	criteria provided, single submitter	clinical testing	The MSH6 c.1474_1476delATG variant is predicted to result in an in-frame deletion (p.Met492del). This variant has been reported in two individuals, one with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754) and another with familial breast cancer (Supplemental Data, Lerner-Ellis et al. 2021. PubMed ID: 32885271). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026592-AATG-A). In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142597/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV001355839	SCV004843666	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of a single amino acid of the MSH6 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 1/251194 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	RCV001355839	SCV001550842	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Met492del variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with a history of Lynch syndrome associated cancer and/or polyps (Yurgelun_2015_25980754). The variant was also identified in dbSNP (ID: rs745312505) “With Uncertain significance allele”, ClinVar (classified as uncertain signficance by Ambry Genetics, GeneDx and Invitae), Clinvitae (3x), Insight Hereditary Tumors Database (2X), and in control databases in 1 of 245948 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017), identified in the African population in 1 of 15302 chromosomes (freq: 0.00007), while not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (Non-Finnish), Latino, Other, and South Asian populations. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant Database. This variant is an in-frame deletion resulting in the removal of a methionine (met) residue at codon 492; the impact of this alteration on MSH6 protein function is not known. The 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.