rs876658719

Variant names:

• chr2-47403310-G-A
• rs876658719
• NM_000251.3:c.119G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47403310-G-A
• chr2-47403310-G-C
• chr2-47403310-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000251.3(MSH2):​c.119G>A​(p.Gly40Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.43

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.119G>A	p.Gly40Asp	missense_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.119G>A	p.Gly40Asp	missense_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Oct 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 40 of the MSH2 protein (p.Gly40Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 934948). -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 25, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G40D variant (also known as c.119G>A), located in coding exon 1 of the MSH2 gene, results from a G to A substitution at nucleotide position 119. The glycine at codon 40 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.5	D;.;D
REVEL	Pathogenic	0.70
Sift	Benign	0.083	T;.;T
Sift4G	Benign	0.18	T;.;T
Polyphen		0.76	P;.;P
Vest4		0.51
MutPred		0.96		Gain of phosphorylation at T44 (P = 0.1655);Gain of phosphorylation at T44 (P = 0.1655);Gain of phosphorylation at T44 (P = 0.1655);
MVP		0.92
MPC		0.023
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.48
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876658719; hg19: chr2-47630449;