2-47412474-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000251.3(MSH2):​c.706G>T​(p.Asp236Tyr) variant causes a missense change involving the alteration of a 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: 32)

Consequence

MSH2
NM_000251.3 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.62
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.706G>T p.Asp236Tyr missense_variant Exon 4 of 16 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkc.706G>T p.Asp236Tyr missense_variant Exon 4 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Dec 14, 2017
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.706G>T (p.D236Y) alteration is located in exon 4 (coding exon 4) of the MSH2 gene. This alteration results from a G to T substitution at nucleotide position 706, causing the aspartic acid (D) at amino acid position 236 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;.;.;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.88
D;D;D;D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Pathogenic
3.2
M;.;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-7.5
D;D;.;D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
D;D;.;D
Sift4G
Uncertain
0.0030
D;D;.;D
Polyphen
1.0
D;.;.;D
Vest4
0.92
MutPred
0.50
Loss of disorder (P = 0.0309);.;Loss of disorder (P = 0.0309);Loss of disorder (P = 0.0309);
MVP
0.98
MPC
0.032
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.96
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.19
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: chr2-47639613; COSMIC: COSV104373278; COSMIC: COSV104373278; API