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NM_000251.3(MSH2):c.1808A>C (p.Asp603Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jun 24, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002408984.2

Allele description [Variation Report for NM_000251.3(MSH2):c.1808A>C (p.Asp603Ala)]

NM_000251.3(MSH2):c.1808A>C (p.Asp603Ala)

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.1808A>C (p.Asp603Ala)
HGVS:
  • NC_000002.12:g.47475073A>C
  • NG_007110.2:g.76950A>C
  • NM_000251.3:c.1808A>CMANE SELECT
  • NM_001258281.1:c.1610A>C
  • NP_000242.1:p.Asp603Ala
  • NP_000242.1:p.Asp603Ala
  • NP_001245210.1:p.Asp537Ala
  • LRG_218t1:c.1808A>C
  • LRG_218:g.76950A>C
  • LRG_218p1:p.Asp603Ala
  • NC_000002.11:g.47702212A>C
  • NM_000251.1:c.1808A>C
  • NM_000251.2:c.1808A>C
Protein change:
D537A
Links:
dbSNP: rs267607985
NCBI 1000 Genomes Browser:
rs267607985
Molecular consequence:
  • NM_000251.3:c.1808A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.1610A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002713207Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jun 24, 2021) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Ambry Genetics, SCV002713207.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.D603A variant (also known as c.1808A>C), located in coding exon 12 of the MSH2 gene, results from an A to C substitution at nucleotide position 1808. The aspartic acid at codon 603 is replaced by alanine, an amino acid with dissimilar properties. Another alteration at the same position, p.D603G, has been reported as likely pathogenic based on identification in a family with Lynch syndrome and reduced function in yeast-based assays (Zhang CH et al. World J. Gastroenterol. 2008 Jan;14:298-302; Arlow T et al. Proc. Natl. Acad. Sci. U.S.A. 2013 Jan;110:246-51). The p.D603Y likely pathogenic variant, also at the same position, has been identified somatically in colorectal tumors that displayed high microsatellite instability (MSI-H) and/or loss of MSH2 protein expression on immunohistochemistry (IHC) (Ambry internal data; Yuen ST et al. Oncogene. 2002 Oct;21:7585-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024