2-47482858-C-G

Position:

chr2-47482858-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000251.3(MSH2):c.2714C>G(p.Thr905Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,613,208 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:6

Conservation

PhyloP100: 0.936

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 links:

MSH2 (HGNC:):

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP6

Variant 2-47482858-C-G is Benign according to our data. Variant chr2-47482858-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 91037.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47482858-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2714C>G	p.Thr905Arg	missense_variant	16/16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.2714C>G	p.Thr905Arg	missense_variant	16/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250742

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135544

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

193

AN:

1461160

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Nov 24, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 06, 2020	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2023	- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 28, 2023

This missense variant replaces threonine with arginine at codon 905 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not significantly impact MSH2 activity as determined by in vitro mismatch repair activity, ATPase activity and interaction with its binding partners (PMID: 9774676, 12124176). This variant has been reported in a family affected with hereditary non-polyposis colon cancer syndrome (PMID: 8880570). This variant has been identified in 3/282122 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

This variant is associated with the following publications: (PMID: 32849802, 16995940, 26333163, 14526391, 20459533, 11162093, 22290698, 17101317, 8880570, 17594722, 12124176, 9774676, 24362816) -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.20

N;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.32

N;N

REVEL

Uncertain

0.51

Sift

Benign

0.36

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.0

B;.

Vest4

0.68

MutPred

0.85

Loss of loop (P = 9e-04);.;

MVP

1.0

MPC

0.0062

ClinPred

0.047

GERP RS

2.5

Varity_R

0.11

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over