rs863224641

chr2-47478448-C-Achr2-47478448-C-Gchr2-47478448-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000251.3(MSH2):c.2387C>A(p.Thr796Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T796A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.69

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 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 14 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3257692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2387C>A	p.Thr796Asn	missense_variant	14/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2387C>A	p.Thr796Asn	missense_variant	14/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2019

This sequence change replaces threonine with asparagine at codon 796 of the MSH2 protein (p.Thr796Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MSH2-related conditions. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2020

The p.T796N variant (also known as c.2387C>A), located in coding exon 14 of the MSH2 gene, results from a C to A substitution at nucleotide position 2387. The threonine at codon 796 is replaced by asparagine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Benign	-0.14
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T;.;.;.
Eigen	Benign	-0.075
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-0.86	N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N;N;.;D
REVEL	Uncertain	0.44
Sift	Benign	0.17	T;T;.;T
Sift4G	Benign	0.40	T;T;.;T
Polyphen		0.23	B;.;.;P
Vest4		0.64
MutPred		0.49		Loss of glycosylation at T796 (P = 0.0096);.;Loss of glycosylation at T796 (P = 0.0096);Loss of glycosylation at T796 (P = 0.0096);
MVP		0.80
MPC		0.013
ClinPred		0.71	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.79

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: rs863224641; hg19: chr2-47705587;