2-47403402-G-A

Position:

• chr2-47403402-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000251.3(MSH2):​c.211G>A​(p.Gly71Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Synonymous variant affecting the same amino acid position (i.e. G71G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.37

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47403402-G-A is Pathogenic according to our data. Variant chr2-47403402-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3065347.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.211G>A	p.Gly71Arg	missense_variant, splice_region_variant	1/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.211G>A	p.Gly71Arg	missense_variant, splice_region_variant	1/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.000553 Hom.: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;T;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.9	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D;D;D;.;D
REVEL	Pathogenic	0.73
Sift	Benign	0.074	T;D;D;.;T
Sift4G	Uncertain	0.019	D;D;D;.;D
Polyphen		0.11	B;.;.;.;D
Vest4		0.39
MutPred		0.53		Gain of MoRF binding (P = 0.0334);.;.;Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);
MVP		0.89
MPC		0.0079
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.75
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -17
DS_DL_spliceai		0.23		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782659; hg19: chr2-47630541;