rs587782278

chr2-47429935-C-Achr2-47429935-C-Gchr2-47429935-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000251.3(MSH2):c.1270C>A(p.His424Asn) 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. 12/21 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. H424Y) 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: 2.09

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 14 uncertain 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 chr2-47429935-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2070866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1270C>A	p.His424Asn	missense_variant	7/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1270C>A	p.His424Asn	missense_variant	7/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Uncertain	0.58	D;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Benign	1.1	L;.;.;.
MutationTaster	Benign	0.59	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D;D;.;D
REVEL	Uncertain	0.44
Sift	Benign	0.29	T;T;.;T
Sift4G	Benign	0.29	T;T;.;T
Polyphen		0.0010	B;.;.;B
Vest4		0.56
MutPred		0.41		Loss of disorder (P = 0.1115);.;Loss of disorder (P = 0.1115);Loss of disorder (P = 0.1115);
MVP		0.87
MPC		0.0065
ClinPred		0.29	T
GERP RS		2.4
Varity_R		0.53
gMVP		0.33

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: chr2-47657074;