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NM_000251.3(MSH2):c.1A>T (p.Met1Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 3, 2022
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:
RCV002415556.2

Allele description [Variation Report for NM_000251.3(MSH2):c.1A>T (p.Met1Leu)]

NM_000251.3(MSH2):c.1A>T (p.Met1Leu)

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.1A>T (p.Met1Leu)
HGVS:
  • NC_000002.12:g.47403192A>T
  • NG_007110.2:g.5069A>T
  • NM_000251.3:c.1A>TMANE SELECT
  • NM_001258281.1:c.-31+17A>T
  • NP_000242.1:p.Met1Leu
  • NP_000242.1:p.Met1Leu
  • LRG_218t1:c.1A>T
  • LRG_218:g.5069A>T
  • LRG_218p1:p.Met1Leu
  • NC_000002.11:g.47630331A>T
  • NM_000251.1:c.1A>T
  • NM_000251.2:c.1A>T
Protein change:
M1L
Links:
dbSNP: rs267607911
NCBI 1000 Genomes Browser:
rs267607911
Molecular consequence:
  • NM_000251.3:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001258281.1:c.-31+17A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000251.3:c.1A>T - 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
SCV002721819Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Mar 3, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO.

Am J Hum Genet. 2021 Jan 7;108(1):163-175. doi: 10.1016/j.ajhg.2020.12.003. Epub 2020 Dec 23.

PubMed [citation]
PMID:
33357406
PMCID:
PMC7820803

Details of each submission

From Ambry Genetics, SCV002721819.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The p.M1? variant (also known as c.1A>T) is located in coding exon 1 of the MSH2 gene and results from a A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). Alterations at the initiation codon of MSH2 have been identified in several cancer cohorts including ovarian cancer, early-onset colorectal cancer (diagnosed under age 30) and known or suspected Lynch syndrome cases; however, tumors do not consistently demonstrate a pattern of MSI and mismatch repair protein-deficient IHC staining (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep 63(3):749-59; Otway R et al. Hum. Mutat. 2000;16(1):61-7; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354(26):2751-63; Barnetson RA et al. Hum. Mutat. 2008 Mar;29(3):367-74; Pal T et al. Br. J. Cancer. 2012 Nov;107(10):1783-90; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). Further, transfection of a similar alteration impacting the initiation codon of MSH2, c.1A>C, cDNA into an MSH2-null, human endometrial cancer cell line showed slight, but statistically significant decrease in repair of an exogenous mismatched protein. This attenuated effect may be due to partial function of the truncated protein and/or expression of the full-length protein resulting from weak translation at the altered, non-AUG start codon, which was detected concomitantly with the truncated protein in this study (Cyr JL et al. Mol. Carcinog. 2012 Aug;51(8):647-58). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

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

Last Updated: Sep 29, 2024