NM_000251.3(MSH2):c.362A>G (p.Tyr121Cys) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 29, 2023
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:: RCV003387764.1

Allele description [Variation Report for NM_000251.3(MSH2):c.362A>G (p.Tyr121Cys)]

NM_000251.3(MSH2):c.362A>G (p.Tyr121Cys)

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.362A>G (p.Tyr121Cys)

Other names:

p.Y121C:TAT>TGT

HGVS:

NC_000002.12:g.47408551A>G
NG_007110.2:g.10428A>G
NM_000251.3:c.362A>GMANE SELECT
NM_001258281.1:c.164A>G
NP_000242.1:p.Tyr121Cys
NP_000242.1:p.Tyr121Cys
NP_001245210.1:p.Tyr55Cys
LRG_218t1:c.362A>G
LRG_218:g.10428A>G
LRG_218p1:p.Tyr121Cys
NC_000002.11:g.47635690A>G
NM_000251.1:c.362A>G
NM_000251.2:c.362A>G

Protein change:

Y121C

Links:

dbSNP: rs587779971

NCBI 1000 Genomes Browser:

rs587779971

Molecular consequence:

NM_000251.3:c.362A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.164A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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LOC126981568 [Eriocheir sinensis]
LOC126981568 [Eriocheir sinensis]
Gene ID:126981568

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004100269	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Sep 29, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24326041, 30584090 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004100269

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Sep 29, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Evaluation of ultra-deep targeted sequencing for personalized breast cancer care.

Harismendy O, Schwab RB, Alakus H, Yost SE, Matsui H, Hasteh F, Wallace AM, Park HL, Madlensky L, Parker B, Carpenter PM, Jepsen K, Anton-Culver H, Frazer KA.

Breast Cancer Res. 2013 Dec 10;15(6):R115. doi: 10.1186/bcr3584.

PubMed [citation]

PMID:: 24326041
PMCID:: PMC3978701

Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors.

Li C, Bonazzoli E, Bellone S, Choi J, Dong W, Menderes G, Altwerger G, Han C, Manzano A, Bianchi A, Pettinella F, Manara P, Lopez S, Yadav G, Riccio F, Zammataro L, Zeybek B, Yang-Hartwich Y, Buza N, Hui P, Wong S, Ravaggi A, et al.

Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):619-624. doi: 10.1073/pnas.1814027116. Epub 2018 Dec 24. Erratum in: Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5829. doi: 10.1073/pnas.1902633116.

PubMed [citation]

PMID:: 30584090
PMCID:: PMC6329978

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004100269.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: MSH2 c.362A>G (p.Tyr121Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250740 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.362A>G has been reported in the literature in individuals affected with breast and ovarian cancer without strong evidence for causality (examples: Harismendy_2013 and Li_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24326041, 30584090). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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