NM_000251.3:c.1849G>A

Variant names:

• chr2-47475114-G-A
• NM_000251.3:c.1849G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Moderate BP6_Moderate

The NM_000251.3(MSH2):​c.1849G>A​(p.Val617Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.07

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 0 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0966036).
• BP6: Variant 2-47475114-G-A is Benign according to our data. Variant chr2-47475114-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2496168.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.1849G>A	p.Val617Ile	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.1849G>A	p.Val617Ile	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: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Dec 21, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	14
DANN	Benign	0.56
DEOGEN2	Benign	0.30	T;.;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.097	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.17	N;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.27	N;N;.;N
REVEL	Uncertain	0.38
Sift	Benign	0.55	T;T;.;T
Sift4G	Benign	0.68	T;T;.;T
Polyphen		0.0	B;.;.;B
Vest4		0.50
MutPred		0.34		Loss of phosphorylation at Y619 (P = 0.1329);.;Loss of phosphorylation at Y619 (P = 0.1329);Loss of phosphorylation at Y619 (P = 0.1329);
MVP		0.79
MPC		0.0069
ClinPred		0.32	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.50

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: chr2-47702253;