rs1442557180

Positions:

• chr2-47403392-G-A
• chr2-47403392-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_001258281.1(MSH2):​c.3G>A​(p.Met1?) variant causes a start lost 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_001258281.1 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001258281.1 (MSH2) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.201G>A	p.Met67Ile	missense_variant	1/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.201G>A	p.Met67Ile	missense_variant	1/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;T;.;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;D;D;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.24	N;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.35	N;N;N;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.23	T;T;T;.;T
Sift4G	Benign	0.21	T;T;T;.;T
Polyphen		0.0	B;.;.;.;B
Vest4		0.081
MutPred		0.61		Gain of catalytic residue at P69 (P = 0.042);.;.;Gain of catalytic residue at P69 (P = 0.042);Gain of catalytic residue at P69 (P = 0.042);
MVP		0.85
MPC		0.0063
ClinPred		0.12	T
GERP RS		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.46
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr2-47630531;