rs766349734

chr2-47410185-C-Achr2-47410185-C-Gchr2-47410185-C-T

Variant summary

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

The NM_000251.3(MSH2):c.458C>A(p.Ser153Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S153C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.14

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 16 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.458C>A	p.Ser153Tyr	missense_variant	3/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.458C>A	p.Ser153Tyr	missense_variant	3/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;T;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.1	D;D;D;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0080	D;D;D;.;D
Sift4G	Uncertain	0.033	D;D;D;.;D
Polyphen		0.26	B;.;.;.;P
Vest4		0.47
MutPred		0.53		Gain of solvent accessibility (P = 0.039);.;.;Gain of solvent accessibility (P = 0.039);Gain of solvent accessibility (P = 0.039);
MVP		0.95
MPC		0.0062
ClinPred		0.90	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.71
gMVP		0.60

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: chr2-47637324;