rs1553356673

Positions:

• chr2-47429871-A-C
• chr2-47429871-A-G
• chr2-47429871-A-T

Variant summary

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

The NM_000251.3(MSH2):​c.1206A>C​(p.Gln402His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.935

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 2 ACMG points.

• 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.1206A>C	p.Gln402His	missense_variant	7/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1206A>C	p.Gln402His	missense_variant	7/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 04, 2020

This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 665472). This sequence change replaces glutamine with histidine at codon 402 of the MSH2 protein (p.Gln402His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.;.;.
Eigen	Benign	-0.0096
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.8	M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D;D;.;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0090	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;.;D
Polyphen		0.059	B;.;.;B
Vest4		0.78
MutPred		0.58		Gain of catalytic residue at D403 (P = 0.0575);.;Gain of catalytic residue at D403 (P = 0.0575);Gain of catalytic residue at D403 (P = 0.0575);
MVP		0.99
MPC		0.011
ClinPred		0.97	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.53

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: rs1553356673; hg19: chr2-47657010;