Submissions for variant NM_000251.3(MSH2):c.1200C>G (p.Asn400Lys)

gnomAD frequency: 0.00002  dbSNP: rs1301023135

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574450	SCV000669734	likely benign	Hereditary cancer-predisposing syndrome	2022-01-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819870	SCV000960553	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001813789	SCV002061054	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no impact on mismatch repair function (PMID: 33357406); This variant is associated with the following publications: (PMID: 18822302, 21120944, 33357406)
PreventionGenetics, part of Exact Sciences	RCV004543264	SCV004778359	uncertain significance	MSH2-related disorder	2024-01-05	criteria provided, single submitter	clinical testing	The MSH2 c.1200C>G variant is predicted to result in the amino acid substitution p.Asn400Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355796	SCV001550780	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Asn400Lys variant was not identified in the literature nor was it identified in the dbSNP, COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors database. The variant was identified in ClinVar (1x as uncertain significance by Ambry Genetics) and LOVD 3.0 (1x). The variant was identified in control databases in 4 of 277132 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24030 chromosomes (freq: 0.0001) and European in 1 of 126630 chromosomes (freq: 0.000008), but not in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was identified by our lab in an individual with an MLH1/PMS2 deficient rectal tumour with a co-occurring pathogenic MLH1 variant (c.1790G>A, p.Trp597*), increasing the likelihood that the p.Asn400Lys variant does not have clinical significance. The p.Asn400 residue is conserved in mammals and 4 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.