Submissions for variant NM_000251.3(MSH2):c.970_971del (p.Gln324fs)

dbSNP: rs63751044

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076767	SCV000107805	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194002	SCV001363218	pathogenic	Hereditary nonpolyposis colon cancer	2019-02-21	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.970_971delCA (p.Gln324ValfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 246216 control chromosomes (gnomAD). c.970_971delCA has been reported in the literature as a recurrent/founder mutation in the Israeli population, exclusively found in Jewish families of Russian Georgian ancestry, where it was found in several individuals affected with Lynch Syndrome (Goldberg 2008, Goldberg 2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001385672	SCV001585617	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-07-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15929773, 18389388). This variant is also known as 324delCA. ClinVar contains an entry for this variant (Variation ID: 91262). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln324Valfs*8) in the MSH2 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics	RCV002381388	SCV002695207	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	The c.970_971delCA pathogenic mutation, located in coding exon 6 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 970 to 971, causing a translational frameshift with a predicted alternate stop codon (p.Q324Vfs*8). This alteration was identified in an Israeli patient whose personal/family history meets Amsterdam criteria (Goldberg Y et al. Fam. Cancer. 2008 Apr;7:309-17). This alteration was identified also in one unaffected control patient in a case-control study of pancreatic cancer patients undergoing multigene panel testing for hereditary cancer risk (Hu C et al. JAMA. 2018 06;319:2401-2409). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003452981	SCV004188081	pathogenic	Lynch syndrome 1	2023-07-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.