rs587782396

Variant names:

• chr2-47476539-G-A
• rs587782396
• NM_000251.3:c.2178G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47476539-G-A
• chr2-47476539-G-C
• chr2-47476539-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PM1 PM2 PP3_Strong BP6_Very_Strong

The NM_000251.3(MSH2):​c.2178G>A​(p.Met726Ile) 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M726L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.60

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 16 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• BP6: Variant 2-47476539-G-A is Benign according to our data. Variant chr2-47476539-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 408484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2178G>A	p.Met726Ile	missense_variant	Exon 13 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2178G>A	p.Met726Ile	missense_variant	Exon 13 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Benign:1

Dec 12, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.2	H;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.7	D;D;.;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.93
MutPred		0.88		Loss of catalytic residue at V722 (P = 0.1158);.;Loss of catalytic residue at V722 (P = 0.1158);Loss of catalytic residue at V722 (P = 0.1158);
MVP		0.96
MPC		0.034
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97

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: rs587782396; hg19: chr2-47703678;