ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3934_3937dup (p.Ile1313fs) (rs760190301)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491551 SCV000580280 pathogenic Hereditary cancer-predisposing syndrome 2017-01-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000491551 SCV000685463 pathogenic Hereditary cancer-predisposing syndrome 2016-06-20 criteria provided, single submitter clinical testing
GeneDx RCV000486034 SCV000565801 pathogenic not provided 2016-03-29 criteria provided, single submitter clinical testing This duplication of 4 nucleotides in MSH6 is denoted c.3934_3937dupGTTA at the cDNA level and p.Ile1313SerfsX7 (I1313SfsX7) at the protein level. The normal sequence, with the bases that are duplicated in braces, is GGAA[GTTA]TTCA. The duplication causes a frameshift which changes an Isoleucine to a Serine at codon 1313, and creates a premature stop codon at position 7 of the new reading frame. Even though mRNA nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 48 amino acids are no longer translated correctly, and it is predicted to cause loss of normal protein function through protein truncation. This variant disrupts an MSH2 binding site in domain V of the MutS domain (Kariola 2002, Terui 2013). MSH6 c.3934_3937dupGTTA has been observed in at least two individuals with a clinical history of a Lynch syndrome-associated cancer and/or colon polyps, one of whom was also diagnosed with breast cancer (Susswein 2015, Yurgelun 2015). The adjacent variant MSH6 c.3932_3935dupAAGT, which also results in a frameshift at this residue (p.Ile1313SerfsX7), was observed in at least two individuals from a single family, one of whom had a diagnosis of colorectal or endometrial cancer (Ramsoekh 2008). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000629708 SCV000750664 pathogenic Hereditary nonpolyposis colon cancer 2018-08-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH6 gene (p.Ile1313Serfs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acids of the MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 28369758), in individuals with a personal and/or family history of Lynch syndrome-associated cancers (PMID: 25980754, 26681312) and in individuals in the Universal Mutation Database (PMID: 23554159). ClinVar contains an entry for this variant (Variation ID: 418610). This variant disrupts a significant C-terminal portion of the MSH2 interaction domain of the MSH6 protein (residues Ala1302-Leu1360) (PMID: 9774676, 12019211). Although functional studies have not been performed for this particular variant, a founder mutation that disrupts the final 31 amino acid residues of the protein (p.Leu1330Valfs*12) has been determined to be pathogenic (PMID: 19851887, 21155762), indicating that these residues are critical for MSH6 function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825625 SCV000966979 pathogenic Lynch syndrome 2018-10-17 criteria provided, single submitter clinical testing The p.Ile1313SerfsX7 variant in MSH6 has been reported in the heterozygous state in 2 individuals with clinical features of Lynch syndrome and in the homozygous state in one individual with constitutional mismatch repair deficiency syndrome (CMMRD; Yurgelun 2015, Susswein 2015, Polubothu 2017). This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID: 418610) and was absent from large population databases. In vitro functional studies provide some evidence that the p.Ile1313SerfsX7 variant may impact protein function by disrupting the MSH2 interaction domain of MSH6 (Guerrette 1998). However, these types of assays may not accurately represent biological function. This variant i s predicted to cause a frameshift, which alters the protein?s amino acid sequenc e beginning at position 1313 and leads to a premature termination codon 7 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NM D) and result in a truncated protein. Another variant at this position (c.3932_3 935dupAAGT), resulting in the same amino acid change, was classified as pathogen ic on Sept 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108166.2) . In summary, this variant meets criteria to be classified as pathogenic for Lyn ch Syndrome in an autosomal dominant manner based upon its presence in affected individuals, absence from the general population, functional evidence, having th e same amino acid change as an established pathogenic variant and the predicted impact on the protein. ACMG/AMP Criteria applied: PS1, PVS1_Strong, PM2, PS3_Su pporting, PS4_Supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486034 SCV000601591 pathogenic not provided 2017-06-15 criteria provided, single submitter clinical testing

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