2-47403340-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2PP3_StrongBP6

The NM_000251.3(MSH2):c.149C>T(p.Ala50Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A50E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 7.26

Publications

4 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

BP6

Variant 2-47403340-C-T is Benign according to our data. Variant chr2-47403340-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1339150.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000432

AC:

AN:

231462

AF XY:

0.00000790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000505

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454992

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

43734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25812

East Asian (EAS)

AF:

0.00

AC:

AN:

39470

South Asian (SAS)

AF:

0.00

AC:

AN:

84744

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110358

Other (OTH)

AF:

0.00

AC:

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 1

Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.A50V in MSH2 (NM_000251.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.A50V variant is observed in 1/19,798 (0.0051%) alleles from individuals of Finnish background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.A50V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 50 of MSH2 is conserved in all mammalian species. The nucleotide c.149 in MSH2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance -

Lynch syndrome

Uncertain:1

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with valine at codon 50 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/231462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 50 of the MSH2 protein (p.Ala50Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1339150). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 333574060) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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. -

Hereditary cancer-predisposing syndrome

Benign:1

Sep 13, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;.;.

PhyloP100

7.3

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.4

D;.;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.84

MutPred

0.82

Loss of disorder (P = 0.1889);Loss of disorder (P = 0.1889);Loss of disorder (P = 0.1889);

MVP

0.98

MPC

0.033

ClinPred

0.99

GERP RS

5.3

PromoterAI

0.028

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.1

Varity_R

0.96

gMVP

0.76

Mutation Taster

=24/76

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over