2-47475203-T-G

Variant names:

• chr2-47475203-T-G
• NM_000251.3:c.1938T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000251.3(MSH2):​c.1938T>G​(p.Asp646Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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 4 ACMG points.

• PM1: In a region_of_interest Interaction with EXO1 (size 70) in uniprot entity MSH2_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1938T>G	p.Asp646Glu	missense_variant	Exon 12 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1938T>G	p.Asp646Glu	missense_variant	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 11, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D646E variant (also known as c.1938T>G), located in coding exon 12 of the MSH2 gene, results from a T to G substitution at nucleotide position 1938. The aspartic acid at codon 646 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is 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	0.19
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.0	L;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.6	D;D;.;D
REVEL	Uncertain	0.60
Sift	Benign	0.13	T;T;.;T
Sift4G	Benign	0.24	T;T;.;T
Polyphen		0.020	B;.;.;P
Vest4		0.58
MutPred		0.61		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.88
MPC		0.0094
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.30
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-47702342;