ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2191C>T (p.Gln731Ter)

dbSNP: rs63751442
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074725 SCV000107933 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000490877 SCV000580333 pathogenic Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing The p.Q731* pathogenic mutation (also known as c.2191C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2191. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation was identified in two related individuals diagnosed with colon cancer at ages 48 and 49 respectively, though the family did not meet ACI or ACII criteria (Wijnen J, Nat. Genet. 1999 Oct; 23(2):142-4; Hendriks YM, Gastroenterology 2004 Jul; 127(1):17-25). This mutation was also identified in a female diagnosed with MSI-stable endometrial cancer at age 56, as well as breast cancer at age 50 (Jóri B, Oncotarget 2015 Dec; 6(38):41108-22). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Invitae RCV001206112 SCV001377404 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant has been observed in several individuals suspected to have Lynch syndrome (PMID: 10508506, 16736289, 26517685). ClinVar contains an entry for this variant (Variation ID: 89261). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln731*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product.
Myriad Genetics, Inc. RCV003450943 SCV004185654 pathogenic Lynch syndrome 5 2023-08-16 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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