2-47412560-G-C

Position:

• chr2-47412560-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000233146.7(MSH2):​c.792G>C​(p.Gln264His) 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q264R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 ENST00000233146.7 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 6.61

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 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 14 uncertain in ENST00000233146.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.792G>C	p.Gln264His	missense_variant, splice_region_variant	4/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.792G>C	p.Gln264His	missense_variant, splice_region_variant	4/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Uncertain:1

Uncertain significance, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 13, 2018

Criteria changed for variants in last base of exon therefore downgrade classification -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N;N;.;N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.010	D;D;.;D
Sift4G	Uncertain	0.039	D;D;.;D
Polyphen		0.97	D;.;.;D
Vest4		0.82
MutPred		0.51		Gain of catalytic residue at Q264 (P = 0.1259);.;Gain of catalytic residue at Q264 (P = 0.1259);Gain of catalytic residue at Q264 (P = 0.1259);
MVP		0.87
MPC		0.0079
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: 17
DS_DL_spliceai		0.54		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: rs587779183; hg19: chr2-47639699;