rs878853824

Positions:

• chr2-47412558-C-G
• chr2-47412558-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000251.3(MSH2):​c.790C>G​(p.Gln264Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. Q264H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense, splice_region
• Scores: Splicing: ADA: 0.03131
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 13) in uniprot entity MSH2_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47412560-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.790C>G	p.Gln264Glu	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.790C>G	p.Gln264Glu	missense_variant, splice_region_variant	4/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

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	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.46	T;.;.;.
Eigen	Benign	0.072
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Uncertain	0.022	D
MutationAssessor	Benign	2.0	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.89	N;N;.;N
REVEL	Uncertain	0.48
Sift	Benign	0.080	T;T;.;T
Sift4G	Benign	0.32	T;T;.;T
Polyphen		0.024	B;.;.;B
Vest4		0.81
MutPred		0.46		Gain of disorder (P = 0.0638);.;Gain of disorder (P = 0.0638);Gain of disorder (P = 0.0638);
MVP		0.86
MPC		0.010
ClinPred		0.61	D
GERP RS		5.5
Varity_R		0.67
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.031
dbscSNV1_RF	Benign	0.26
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: chr2-47639697;