2-47414311-C-T

Position:

• chr2-47414311-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000233146.7(MSH2):​c.835C>T​(p.Leu279Phe) 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 pathogenic 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. L279H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: MSH2 ENST00000233146.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.20

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]

MSH2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.835C>T	p.Leu279Phe	missense_variant	5/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.835C>T	p.Leu279Phe	missense_variant	5/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D;D;.;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0040	D;D;.;D
Sift4G	Uncertain	0.0050	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.76
MutPred		0.51		Gain of methylation at K275 (P = 0.0834);.;Gain of methylation at K275 (P = 0.0834);Gain of methylation at K275 (P = 0.0834);
MVP		0.88
MPC		0.031
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.91
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs375351205; hg19: chr2-47641450;