NM_000251.3(MSH2):c.146A>T (p.Asp49Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 24, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000221403.15

Allele description [Variation Report for NM_000251.3(MSH2):c.146A>T (p.Asp49Val)]

NM_000251.3(MSH2):c.146A>T (p.Asp49Val)

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.146A>T (p.Asp49Val)

Other names:

p.D49V:GAC>GTC

HGVS:

NC_000002.12:g.47403337A>T
NG_007110.2:g.5214A>T
NM_000251.3:c.146A>TMANE SELECT
NM_001258281.1:c.-30-23A>T
NP_000242.1:p.Asp49Val
NP_000242.1:p.Asp49Val
LRG_218t1:c.146A>T
LRG_218:g.5214A>T
LRG_218p1:p.Asp49Val
NC_000002.11:g.47630476A>T
NM_000251.1:c.146A>T
NM_000251.2:c.146A>T

Protein change:

D49V

Links:

dbSNP: rs63750335

NCBI 1000 Genomes Browser:

rs63750335

Molecular consequence:

NM_001258281.1:c.-30-23A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.146A>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000277722	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 24, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17569143, 33471991 Citation Link,
SCV000684939	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 6, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17569143, 20176959, 32268276, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000277722

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 24, 2024)

germline

clinical testing

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

Citation Link,

SCV000684939

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 6, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: implications for genetic testing.

Papp J, Kovacs ME, Olah E.

World J Gastroenterol. 2007 May 21;13(19):2727-32.

PubMed [citation]

PMID:: 17569143
PMCID:: PMC4147123

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000277722.9

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

Description

The p.D49V variant (also known as c.146A>T), located in coding exon 1 of the MSH2 gene, results from an A to T substitution at nucleotide position 146. The aspartic acid at codon 49 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been identified in a Hungarian individual diagnosed with colorectal cancer at age 53 (Papp J et al, World J. Gastroenterol. 2007 May; 13(19):2727-32). Yeast mutator assays testing for MMR defects have shown that this allele results in loss of function (Martinez SL and Kolodner RD. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5070-5). 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 available evidence, the clinical significance of this variant remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV000684939.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces aspartic acid with valine at codon 49 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant has defective DNA damage repair function in a yeast assay (PMID: 20176959). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer (PMID: 17569143) and an individual affected with prostate cancer (PMID: 32268276). This variant has been identified in 2/231720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of 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: Oct 20, 2024

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