Submissions for variant NM_002439.5(MSH3):c.1858G>A (p.Asp620Asn)

gnomAD frequency: 0.00004  dbSNP: rs200337887

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802810	SCV000942655	uncertain significance	not provided	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 620 of the MSH3 protein (p.Asp620Asn). This variant is present in population databases (rs200337887, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 648147). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001013421	SCV001174004	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	The p.D620N variant (also known as c.1858G>A), located in coding exon 13 of the MSH3 gene, results from a G to A substitution at nucleotide position 1858. The aspartic acid at codon 620 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV001816867	SCV002065302	uncertain significance	not specified	2021-05-26	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH3 gene demonstrated a sequence change, c.1858G>A, in exon 13 that results in an amino acid change, p.Asp620Asn. This sequence change has been described in the gnomAD database with a frequency of 0.065% in the East Asian subpopulation (dbSNP rs200337887). The p.Asp620Asn change affects a highly conserved amino acid residue located in a domain of the MSH3 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp620Asn substitution. This sequence change does not appear to have been previously described in patients with MSH3-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp620Asn change remains unknown at this time.
Sema4, Sema4	RCV001013421	SCV002535997	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	curation
GeneDx	RCV000802810	SCV002588025	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with lymphoblastic leukemia (Xue 2022); This variant is associated with the following publications: (PMID: 34608827)
Baylor Genetics	RCV003467392	SCV004196976	uncertain significance	Endometrial carcinoma	2024-03-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005036167	SCV005666193	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-03-01	criteria provided, single submitter	clinical testing