2-47478486-G-A

Position:

chr2-47478486-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000251.3(MSH2):c.2425G>A(p.Glu809Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9O:2

Conservation

PhyloP100: 3.01

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009382755).

BP6

Variant 2-47478486-G-A is Benign according to our data. Variant chr2-47478486-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41648.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=2, Benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2425G>A	p.Glu809Lys	missense_variant	14/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.2425G>A	p.Glu809Lys	missense_variant	14/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000274

AC:

AN:

251372

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00375

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00189

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000138

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000296

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 22, 2020	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2019	Variant summary: MSH2 c.2425G>A (p.Glu809Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251372 control chromosomes, predominantly at a frequency of 0.0038 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7-fold the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2425G>A has been reported in the literature in individuals affected with Lynch Syndrome (Jiang_2019, Liu_2014, Pinard_2016, Tang_2009, Toh_2018, Xie_2018), predominantly in individuals of Asian origin. A database cites the variant to co-occur with a pathogenic variant in MSH2 (c.942+3A>T) and indicated that the variant did not cosegregate with disease in a family. Four ClinVar submissions (evaluation after 2014) cite the variant three times as likely benign and once as benign. Based on the evidence outlined above, the variant was classified as benign. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 30, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 11, 2018	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. -

Lynch syndrome 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Ding PR Lab, Sun Yat-sen University Cancer Center

- -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jul 13, 2012

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

MSH2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Glu809Lys variant was identified in 2 of 304 proband chromosomes (frequency: 0.007) from individuals or families with Lynch syndrome and was present in 4 of 600 control chromosomes (frequency: 0.007) from healthy individuals (Liu 2014, Tang 2009). The variant was also identified in dbSNP (ID: rs202145681) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as benign by Invitae; as likely benign by three submitters; as uncertain significance by one submitter), and in UMD-LSDB (1x as unclassified variant). In UMD the variant was identified with a co-occurring pathogenic MSH2 variant (c.583G>T, p.Gly195X), increasing the likelihood that the p.Glu809Lys variant does not have clinical significance. The variant was identified in control databases in 77 of 277132 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 77 of 18870 chromosomes (freq: 0.004), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Glu809 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary nonpolyposis colon cancer

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Uncertain significance and reported on 06-15-2018 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.41

T;.;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.0094

T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.56

N;.;.;.

MutationTaster

Benign

0.52

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.52

N;N;.;N

REVEL

Uncertain

0.41

Sift

Benign

0.86

T;T;.;T

Sift4G

Benign

1.0

T;T;.;T

Polyphen

0.0030

B;.;.;B

Vest4

0.37

MVP

0.89

MPC

0.0064

ClinPred

0.054

GERP RS

4.4

Varity_R

0.25

gMVP

0.47

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