rs63750347

Positions:

• chr2-47412522-C-A
• chr2-47412522-C-G
• chr2-47412522-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000251.3(MSH2):​c.754C>A​(p.Gln252Lys) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q252H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.49

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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 17 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2652042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.754C>A	p.Gln252Lys	missense_variant	4/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.754C>A	p.Gln252Lys	missense_variant	4/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Uncertain	0.64	D;.;.;.
Eigen	Benign	-0.026
Eigen_PC	Benign	0.079
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N;N;.;N
REVEL	Uncertain	0.52
Sift	Benign	0.29	T;T;.;T
Sift4G	Benign	0.40	T;T;.;T
Polyphen		0.20	B;.;.;P
Vest4		0.62
MutPred		0.38		Gain of ubiquitination at Q252 (P = 0.023);.;Gain of ubiquitination at Q252 (P = 0.023);Gain of ubiquitination at Q252 (P = 0.023);
MVP		0.92
MPC		0.0061
ClinPred		0.60	D
GERP RS		4.6
Varity_R		0.41
gMVP		0.35

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: chr2-47639661;