ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1937A>G (p.Lys646Arg) (rs201096652)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229693 SCV000283737 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 646 of the MSH6 protein (p.Lys646Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs201096652, ExAC 0.07%). This variant has been observed in individual(s) with endometrial and breast cancers (PMID: 31307542, 26689913). ClinVar contains an entry for this variant (Variation ID: 237148). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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.
GeneDx RCV000482874 SCV000565219 likely benign not provided 2018-10-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23621914, 26689913, 29338689, 31386297)
Ambry Genetics RCV000491214 SCV000580205 likely benign Hereditary cancer-predisposing syndrome 2018-07-10 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence
Color Health, Inc RCV000491214 SCV000685240 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-29 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 646 of the MSH6 protein. Computational prediction tool 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 performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26689913) and in an individual affected with endometrial cancer (PMID: 31307542). This variant has been identified in 9/251204 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482874 SCV001134402 uncertain significance not provided 2019-06-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192456 SCV001360592 uncertain significance not specified 2019-07-18 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1937A>G (p.Lys646Arg) results in a conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function, in addition, a bioinformatics tool developed to predict the impact of missense variants in MSH6, indicated no impact on protein function (Terui 2013). The variant allele was found at a frequency of 3.6e-05 in 251204 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.00043 in the gnomAD database, which is higher than the expected maximum for a pathogenic variant in MSH6 (0.00014), supporting a benign role for the variant. c.1937A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (Lu_2015, Wang_2019, Samuel_2019, Yehia_2018), and one of these individuals had a positive family history for colon cancer (Samuel_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH6, p.K1228fs*2), providing supporting evidence for a benign role (Yehia_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000482874 SCV001501269 uncertain significance not provided 2020-11-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356893 SCV001552175 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 p.Lys646Arg variant was not identified in the literature nor was it identified in the GeneInsight-COGR, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs201096652) as “With Uncertain significance allele”, in ClinVar and Clinvitae (classified as uncertain significance by Invitae, GeneDx and Color Genomics; and likely benign by Ambry Genetics), and COSMIC databases (confirmed somatic in one case of gastric adenocarcinoma). The variant was identified in control databases in 8 of 245948 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 7 of 17248 chromosomes (freq: 0.0004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003) while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, or Finnish populations. The p.Lys646 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. 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.

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