ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1822A>G (p.Ile608Val) (rs201613780)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589796 SCV000211282 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1822A>G at the cDNA level, p.Ile608Val (I608V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant was identified in an individual with a personal history of a Lynch syndrome-associated cancer and/or polyps undergoing multi-gene hereditary cancer panel testing (Yurgelun 2015). MSH6 Ile608Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ile608Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located the Connector domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Ile608Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000196510 SCV000254283 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 608 of the MSH6 protein (p.Ile608Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs201613780, ExAC <0.01%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754) and in an individual with breast cancer (PMID: 30374176). ClinVar contains an entry for this variant (Variation ID: 182626). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The valine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Ambry Genetics RCV000491442 SCV000580260 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-10 criteria provided, single submitter clinical testing The p.I608V variant (also known as c.1822A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1822. The isoleucine at codon 608 is replaced by valine, an amino acid with highly similar properties. 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 amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589796 SCV000695797 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1822A>G (p.Ile608Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant, and Ile608 is located in the connector domain of DNA mismatch repair protein Msh6. This variant was found in 1/120584 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant was identified in one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps, but without evidence of causality (Yurgelun_Gastroenterol_2015). In addition, multiple clinical diagnostic laboratories classified this variant as a VUS. Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
University of Washington Department of Laboratory Medicine, University of Washington RCV000757926 SCV000886444 likely benign Lynch syndrome 2018-04-30 criteria provided, single submitter research The MSH6 variant designated as NM_000179.2:c.1822A>G (p.Ile608Val) is classified as likely benign. Based on in-silico scores the variant has a prior probability of pathogenicity of 10% (Thompson et al., 2013, PMID:22949379). Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303). Analysis of one family gave a likelihood ratio of 0.34 to 1 that this allele explains cancer in the family (Thompson, et al., 2003, PMID:2900794). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH6 function or modify cancer risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color Health, Inc RCV000491442 SCV000911114 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-04 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 608 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 Lynch syndrome–associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 8/281964 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 RCV000757926 SCV001550941 uncertain significance Lynch syndrome no assertion criteria provided clinical testing The MSH6 p.Ile608Val variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome-related cancer and/or colorectal polyps (Yurgelun 2015). In this study, the variant co-occurred with a pathogenic MUTYH variant (c.734G>A, p.Arg245His) in the affected individual. The variant was also identified in dbSNP (ID: rs201613780) as “With Uncertain significance allele”, ClinVar (classified as likely benign by University of Washington Dept. of Laboratory Medicine and as uncertain significance by GeneDx, Invitae, Ambry Genetics, Color and Integrated Genetics/Laboratory Corp. of America). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 8 of 276892 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017); observed in the following populations: European Non-Finnish in 7 of 126468 chromosomes (freq: 0.00006) and European Finnish in 1 of 25790 chromosomes (freq: 0.00004), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian or South Asian populations. The p.Ile608 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Val variant impacts the protein; however, 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) 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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