ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3691GTT[1] (p.Val1232del)

dbSNP: rs587779284
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000221540 SCV000279611 uncertain significance not provided 2015-12-22 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in MSH6 is denoted c.3694_3696delGTT at the cDNA level and p.Val1232del (V1232del) at the protein level. The normal sequence, with the bases that are deleted in braces, is AGTT[GTT]AAAG. This deletion of a single Valine residue occurs at a position that is conserved across species and is located within the MutS domain V (Terui 2013). This variant has been observed in at least one individual with endometrial cancer (Buchanan 2014). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Val1232del to be a variant of uncertain significance.
Ambry Genetics RCV000567987 SCV000676137 likely pathogenic Hereditary cancer-predisposing syndrome 2022-12-07 criteria provided, single submitter clinical testing The c.3694_3696delGTT variant (also known as p.V1232del) is located in coding exon 8 of the MSH6 gene. This variant results from an in-frame deletion of 3 nucleotides (GTT) at positions 3694 to 3696, causing the removal of a highly conserved valine residue at codon 1232. This alteration has been identified in several probands with Lynch syndrome-associated tumors that demonstrated isolated loss of MSH6 expression on immunohistochemistry (Ambry internal data; Buchanan DD et al. J. Clin. Oncol., 2014 Jan;32:90-100; Brennan B et al. Therap Adv Gastroenterol, 2017 Apr;10:361-371). Based on an internal structural assessment, this alteration disrupts the structure of the ATPase domain (Ambry internal data; Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000704903 SCV000833875 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-11-25 criteria provided, single submitter clinical testing This variant, c.3694_3696del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Val1232del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 24323032, 28491141; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89448). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity Omics RCV000221540 SCV003833176 likely pathogenic not provided 2022-09-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355382 SCV001550255 uncertain significance Endometrial carcinoma no assertion criteria provided clinical testing The MSH6 p.Val1232del variant was identified in 1 of 1404 proband chromosomes (frequency: 0.0007) from individuals or families with Endometrial cancer (Buchanan 2014). The variant was also identified in dbSNP (ID: rs587779284) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by InSight, geneDx and Ambry Genetics), UMD-LSDB (1x as unclassified variant), and in Insight Hereditary Tumors Database (1x). The variant was not identified in COGR, Cosmic, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion resulting in the removal of a valine (val) residue at codon 1232; the impact of this alteration on MSH6 protein function is not known. In addition, 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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