2-47480827-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000251.3(MSH2):c.2590G>C(p.Asp864His) variant causes a missense change. 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. D864G) 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: 5.21

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 2 ACMG points.

• 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.2590G>C	p.Asp864His	missense_variant	15/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2590G>C	p.Asp864His	missense_variant	15/16	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	0.14
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	0.53	D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.2	D;D;.;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Benign	0.070	T;T;.;D
Polyphen		0.80	P;.;.;P
Vest4		0.45
MutPred		0.36		Gain of catalytic residue at M866 (P = 0.0446);.;Gain of catalytic residue at M866 (P = 0.0446);Gain of catalytic residue at M866 (P = 0.0446);
MVP		0.92
MPC		0.0087
ClinPred		0.89	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.37

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: chr2-47707966;