ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3744_3773del (p.His1248_Ser1257del) (rs863225412)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657120 SCV000279910 pathogenic not provided 2021-03-19 criteria provided, single submitter clinical testing In-frame deletion of 10 amino acids in a non-repeat region predicted to critically alter the protein: disrupts the ATPase domain (Warren 2007, Kansikas 2011); In silico analysis supports a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 28765196, 25504618, 29922827)
Ambry Genetics RCV000491301 SCV000580154 pathogenic Hereditary cancer-predisposing syndrome 2020-08-13 criteria provided, single submitter clinical testing The c.3744_3773del30 pathogenic mutation (also known as p.H1248_S1257del) is located in coding exon 8 of the MSH6 gene. This mutation results from an in-frame deletion of 30 nucleotides at positions 3744 to 3773 and causes the removal of 10 well-conserved amino acid residues at codons 1248 to 1257. This mutation has been detected in three families meeting Amsterdam criteria for Lynch syndrome with tumor results from one family showing loss of MSH6 protein on immunohistochemistry (Ambry internal data). This mutation segregated with disease in the three families with a combined LOD score of 1.8 (Ambry internal data). Based on internal structural analysis, this alteration results in a distortion of the α-helix of a protein-protein interface of MSH6, significantly altering the surrounding residues (Warren JJ et al. Mol. Cell. 2007 May; 26(4):579-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000533181 SCV000624910 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-08-08 criteria provided, single submitter clinical testing This sequence change deletes 30 nucleotides from exon 8 of the MSH6 mRNA (c.3744_3773del30). This leads to the deletion of 10 amino acid residues in the MSH6 protein (p.His1248_Ser1257del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families with suspected Lynch syndrome, and segregated with Lynch syndrome-related cancers in several of these families (Invitae, External communication). ClinVar contains an entry for this variant (Variation ID: 218070). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375485 SCV000917780 likely pathogenic Hereditary nonpolyposis colon cancer 2021-04-08 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3744_3773del30 (p.His1248_Ser1257del) results in an in-frame deletion that is predicted to remove 10 amino acids from the encoded protein. The variant allele was found at a frequency of 4e-06 in 251206 control chromosomes. c.3744_3773del30 has been reported in the literature in individuals affected with Lynch Syndrome (Chang_2018). These data do not allow any conclusion about variant significance. Co-occurrences with a pathogenic variant has been reported (APC c.487C>T, p.Gln163X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and indicated that this variant co-segregates with lynch syndrome-related cancers in multiple families. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202077 SCV000257276 uncertain significance not specified no assertion criteria provided research

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