Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV001526386 | SCV001736714 | likely pathogenic | Lynch syndrome | 2021-06-07 | criteria provided, single submitter | clinical testing | The c.[3601C>G;3724C>A] (p.[Leu1201Val;Arg1242Ser]) haplotype variant in MSH6 has been identified in at least 10 individuals with clinical features of Lynch syndrome, including 2 individuals with constitutional mismatch repair deficiency syndrome who carried another pathogenic MSH6 variant on the other allele (O'Leary 2014, Turner 2018 PMID 29875428; internal data from University of Washington, Invitae and Ambry (SCV000276654.6)). Tumors sampled from affected individuals with this variant lacked MSH6 expression by IHC (Invitae internal data). This haplotype variant has also been identified in 1/15432 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4_Moderate, PM3, PM2_Supporting, PP4. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323897 | SCV004030072 | likely pathogenic | Hereditary nonpolyposis colon cancer | 2023-07-18 | criteria provided, single submitter | clinical testing | Variant summary: MSH6 c.[3601C>G;3724C>A] (p.[Leu1201Val;Arg1242Ser]) variant is a complex allele that involves the alteration of multiple nucleotides. The component variants of the complex allele were found at a frequency of ~3.2e-05 in 31336 control chromosomes (gnomAD, genomes dataset), i.e. both variants were reported in one heterozygous sample (from the same subpopulation, same gender and age group, therefore, it can be concluded that it likely represented the complex haplotype). The complex variant c.[3601C>G;3724C>A], or the two component variants, have been reported in the literature in multiple heterozygous individuals affected with Lynch Syndrome related tumors (e.g. OLeary_2014 [No PMID], Turner_2019, Gordon_2019, Li_2020). In addition, the complex was also reported in a case with childhood glioma, who carried a second pathogenic MSH6 variant in trans (Crotty_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMIDs: 29875428, 31422818, 31391288, 32556862, 34994648). One submitter has cited clinical-significance assessments for the complex variant to ClinVar after 2014 and has classified the variant as likely pathogenic [ClinVar variation ID: 1172512]. In addition, several clinical laboratories reported the component variants as frequently observed in cis in affected individuals, citing internal data [ClinVar variation IDs: 89423, 89449]. Based on the evidence outlined above, the variant was classified as likely pathogenic. |