2-47403203-G-T

Variant names:

• chr2-47403203-G-T
• rs878853800
• NM_000251.3:c.12G>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_000251.3(MSH2):​c.12G>T​(p.Gln4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.23

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37977555).
• BP6: Variant 2-47403203-G-T is Benign according to our data. Variant chr2-47403203-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 619517.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.12G>T	p.Gln4His	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.12G>T	p.Gln4His	missense_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445250 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717554

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: 0.0000120

Gnomad4 FIN exome AF: 0.0000198

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lynch syndrome Benign:1

May 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH2 NM_000251.2:c.12G>T has a 3.2% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 0.16 and 0.20 to 1, generated from evidence of seeing this as a somatic mutation in independent tumors with and without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0080	D;.;D
Sift4G	Benign	0.23	T;.;T
Polyphen		0.12	B;.;D
Vest4		0.59
MutPred		0.24		Loss of ubiquitination at K6 (P = 0.0547);Loss of ubiquitination at K6 (P = 0.0547);Loss of ubiquitination at K6 (P = 0.0547);
MVP		0.92
MPC		0.017
ClinPred		0.91	D
GERP RS		2.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.55
gMVP		0.55

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: rs878853800; hg19: chr2-47630342;