rs530814648

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6

The NM_000251.3(MSH2):c.817G>A(p.Val273Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: not found (cov: 29)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.30

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a helix (size 13) in uniprot entity MSH2_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_000251.3

BP4

Computational evidence support a benign effect (MetaRNN=0.26719517).

BP6

Variant 2-47414293-G-A is Benign according to our data. Variant chr2-47414293-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246308.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.817G>A	p.Val273Ile	missense_variant	5/16	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.817G>A	p.Val273Ile	missense_variant	5/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250710

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135468

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:

0.000231

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461200

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000221

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 11, 2022	This alteration is classified as 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2018

This variant is denoted MSH2 c.817G>A at the cDNA level, p.Val273Ile (V273I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). MSH2 c.817G>A was observed, in unknown phase, with MSH2 c.818T>A in an individual with a colorectal tumor demonstrating microsatellite instability and loss of MSH2 protein expression (Pigatto 2004, Sharp 2004). Due to the affected bases being adjacent, if the variants are in cis, this would result in MSH2 Val273Lys, and if in trans, this individual would be compound heterozygous for MSH2 Val273Ile and Val273Glu. However, c.817G>A or another nucleotide substitution resulting in MSH2 Val273Ile alone has not, to our knowledge, been reported in the literature. MSH2 Val273Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Val273Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Lynch syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 02, 2023

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Endometrial carcinoma

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Val273Ile variant was identified in dbSNP (ID: rs530814648) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified uncertain significance by GeneDx, Invitae and Ambry Genetics), Clinvitae (2x), and not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 8 of 245604 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017), with breakdown of the observations by population include European Non-Finnish in 1 of 111478 chromosomes (freq: 0.000009) and South Asian in 7 of 30496 chromosomes (freq: 0.0002) while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian and European Finnish, populations. The variant was also identified by our laboratory in 1 individual with endometrial cancer, co-occurring with a pathogenic MLH1 variant (c.588+1G>C). The p.Val273 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 the variant Ile impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. RNA analysis (RT-PCR and allele specific RT-PCR) of peripheral blood RNA, on a cohort of patients with unclassified variants showed that the MSH2 c.817G>A;c.817T>A/p.Val274Lys was associated with normal RNA expression and splicing (Sharp_2004_ 15300854). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.;.;.

Eigen

Benign

-0.021

Eigen_PC

Benign

0.095

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Uncertain

0.030

MutationAssessor

Benign

1.6

L;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

0.20

N;N;.;N

REVEL

Uncertain

0.52

Sift

Benign

0.051

T;D;.;D

Sift4G

Uncertain

0.029

D;D;.;T

Polyphen

0.044

B;.;.;B

Vest4

0.52

MutPred

0.56

Loss of catalytic residue at V273 (P = 0.0237);.;Loss of catalytic residue at V273 (P = 0.0237);Loss of catalytic residue at V273 (P = 0.0237);

MVP

0.89

MPC

0.0074

ClinPred

0.46

GERP RS

4.2

Varity_R

0.24

gMVP

0.20

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