2-47403240-G-T

Position:

• chr2-47403240-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000251.3(MSH2):​c.49G>T​(p.Val17Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.134

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]

MSH2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15910557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.49G>T	p.Val17Phe	missense_variant	1/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.49G>T	p.Val17Phe	missense_variant	1/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447282 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 04, 2019

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 2021

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. This variant has been observed in individual(s) with Lynch syndrome (PMID: 12132870). ClinVar contains an entry for this variant (Variation ID: 91113). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 17 of the MSH2 protein (p.Val17Phe). The valine residue is weakly conserved and there is a small physicochemical difference between valine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.41	T;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.0	L;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.71	T;.;T
Sift4G	Benign	0.082	T;.;T
Polyphen		0.022	B;.;B
Vest4		0.17
MutPred		0.73		Loss of catalytic residue at V17 (P = 0.1938);Loss of catalytic residue at V17 (P = 0.1938);Loss of catalytic residue at V17 (P = 0.1938);
MVP		0.75
MPC		0.0060
ClinPred		0.074	T
GERP RS		-0.24
Varity_R		0.25
gMVP		0.31

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: rs63750966; hg19: chr2-47630379;