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 likely pathogenic not provided 2017-08-15 criteria provided, single submitter clinical testing This in-frame deletion of 30 nucleotides in MSH6 is denoted c.3744_3773del30 at the cDNA level and p.His1248_Ser1257del (H1248_S1257del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CTCA[del30]AAAT. This variant was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). This deletion occurs in a region that is variably conserved and is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses predict that this is probably damaging to protein structure and function. While in-frame deletions may or may not inhibit proper protein functioning, internal clinical data support the classification of MSH6 His1248_Ser1257del as a likely pathogenic variant.
Ambry Genetics RCV000491301 SCV000580154 pathogenic Hereditary cancer-predisposing syndrome 2017-08-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);Good segregation with disease (lod 1.5-3 = 5-9 meioses);Structural Evidence
Invitae RCV000533181 SCV000624910 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-25 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.
Integrated Genetics/Laboratory Corporation of America RCV000202077 SCV000917780 uncertain significance not specified 2018-10-22 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 in the DNA mismatch repair protein MutS, C-terminal domain. The variant allele was found at a frequency of 4.1e-06 in 245976 control chromosomes. c.3744_3773del30 has been reported in the literature, however, this report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome (Hu_2018). Although the reading frame is retained, a missense change at a nearby codon (p.Arg1242His) is classified as likely pathogenic, suggesting amino acids in this region are important for proper gene function. However, an internal specimen was identified as carrying the variant along with a co-occurring pathogenic APC mutation (C. 487C>T, p.Q163X), suggesting the variant of interest may not be responsible for disease. 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 without evidence for independent evaluation with conflicting results (1x pathogenic, 1x likely pathogenic, 1x VUS). Based on the evidence outlined above, the variant was classified as VUS (uncertain significance) until additional data become available.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202077 SCV000257276 uncertain significance not specified no assertion criteria provided research

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