rs879254195

chr2-47403376-G-Achr2-47403376-G-Cchr2-47403376-G-T

Variant summary

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

The NM_000251.3(MSH2):c.185G>A(p.Gly62Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G62A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 15 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.185G>A	p.Gly62Glu	missense_variant	1/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.185G>A	p.Gly62Glu	missense_variant	1/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2016

The p.G62E variant (also known as c.185G>A), located in coding exon 1 of the MSH2 gene, results from a G to A substitution at nucleotide position 185. The glycine at codon 62 is replaced by glutamic acid, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6475 samples (12950 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 115000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.010	D;.;D
Sift4G	Uncertain	0.020	D;.;D
Polyphen		0.66	P;.;D
Vest4		0.68
MutPred		0.58		Loss of MoRF binding (P = 0.1129);Loss of MoRF binding (P = 0.1129);Loss of MoRF binding (P = 0.1129);
MVP		0.86
MPC		0.025
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.83
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.46		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879254195; hg19: chr2-47630515;