rs876659357

Positions:

• chr2-47412537-G-A
• chr2-47412537-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The ENST00000233146.7(MSH2):​c.769G>A​(p.Val257Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V257A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 ENST00000233146.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.13

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 17 uncertain in ENST00000233146.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2648213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.769G>A	p.Val257Ile	missense_variant	4/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.769G>A	p.Val257Ile	missense_variant	4/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 231779). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 257 of the MSH2 protein (p.Val257Ile). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2015

The p.V257I variant (also known as c.769G>A), located in coding exon 4 of the MSH2 gene, results from a G to A substitution at nucleotide position 769. The valine at codon 257 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Benign	0.083
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.;.;.
Eigen	Benign	0.020
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Uncertain	0.012	D
MutationAssessor	Benign	0.83	L;.;.;.
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.65	N;N;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.36	T;T;.;T
Sift4G	Benign	0.15	T;T;.;T
Polyphen		0.012	B;.;.;B
Vest4		0.48
MutPred		0.48		Gain of catalytic residue at P259 (P = 0.0307);.;Gain of catalytic residue at P259 (P = 0.0307);Gain of catalytic residue at P259 (P = 0.0307);
MVP		0.86
MPC		0.0076
ClinPred		0.43	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.27
gMVP		0.19

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: rs876659357; hg19: chr2-47639676;