2-47403391-T-C

Position:

• chr2-47403391-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1 PS1_Moderate PM2 BP6

The NM_001258281.1(MSH2):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_001258281.1 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.45

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 11 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
• BP6: Variant 2-47403391-T-C is Benign according to our data. Variant chr2-47403391-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 820508.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.200T>C	p.Met67Thr	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.200T>C	p.Met67Thr	missense_variant	1/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 16, 2023

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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 820508). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 67 of the MSH2 protein (p.Met67Thr). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;T;.;.;.
Eigen	Benign	0.024
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;D;D;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	0.99	L;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.7	D;D;D;.;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;D;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;.;D
Polyphen		0.074	B;.;.;.;B
Vest4		0.31
MutPred		0.71		Gain of phosphorylation at M67 (P = 0.0958);.;.;Gain of phosphorylation at M67 (P = 0.0958);Gain of phosphorylation at M67 (P = 0.0958);
MVP		0.88
MPC		0.0069
ClinPred		0.92	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.87
gMVP		0.40

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: rs876660001; hg19: chr2-47630530;