2-47414291-C-T

Position:

chr2-47414291-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_ModerateBP6_Very_Strong

The ENST00000233146.7(MSH2):c.815C>T(p.Ala272Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,612,784 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A272T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00042 ( 1 hom., cov: 29)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

MSH2
ENST00000233146.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:5B:16

Conservation

PhyloP100: 7.65

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 Benign. Variant got -8 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 14 uncertain in ENST00000233146.7

BP4

Computational evidence support a benign effect (MetaRNN=0.2501289).

BP6

Variant 2-47414291-C-T is Benign according to our data. Variant chr2-47414291-C-T is described in ClinVar as [Benign]. Clinvar id is 41651.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47414291-C-T is described in Lovd as [Likely_benign]. Variant chr2-47414291-C-T is described in Lovd as [Pathogenic]. Variant chr2-47414291-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-47414291-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.815C>T	p.Ala272Val	missense_variant	5/16	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.815C>T	p.Ala272Val	missense_variant	5/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.000415

AC:

AN:

151678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000303

AC:

AN:

250724

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

135486

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000406

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000251

AC:

367

AN:

1461106

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

174

AN XY:

726828

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000314

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000279

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000415

AC:

AN:

151678

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

AN XY:

74040

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000410

Hom.:

Bravo

AF:

0.000593

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Uncertain:5Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	Variant classified as Uncertain Significance - Favor Benign. The p.Ala272Val variant in MSH2 has been reported in at least 11 individuals with Lynch Syndrome-related cancers (Ollila 2006, Mueller 2009, InSiGHT database (http://chromium.lovd.nl/LOVD2/colon_cancer/variants.php)). One of these patients carried a second pathogenic variant in MLH1. In vitro functional studies provide some evidence that the p.Ala272Val variant may have a slight impact on the protein (Tournier 2008, Lastella 2006), however others demonstrate an effect comparable to that in the wild-type (Ollila 2006). These types of assays may not accurately represent biological function. This variant has been identified in 11/10358 Ashkenazi Jewish chromosomes (0.1%) by the Genome Aggregation Consortium (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In addition, it has been classified as Uncertain Significance on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107764.2). In summary, the clinical significance of the p.Ala272Val variant is uncertain. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2021	Variant summary: MSH2 c.815C>T (p.Ala272Val) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 252008 control chromosomes, predominantly at a frequency of 0.00041 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is close to that estimated for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00041 vs 0.00057), supporting a benign role for the variant of interest. c.815C>T has been reported in the literature in individuals affected with Lynch Syndrome, as well as colorectal-, pancreatic-, breast- and skin cancers (example, Lin_1999, Ollila_2006, Nilbert_2009, Samowitz_2001, Syngal_1999, Yang_2016, Dominguez-Valentin_2018, Cho_2018, Young_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. <ultiple co-occurrences with other pathogenic variants have been reported (MSH2 c.518T>G / p.Leu173Arg, in the UMD database; MLH1 del exon 6, Mueller_2009; BRCA2 c.9382C>T / p.Arg3128X, Domingues-Valentin_2018), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating the impact of MSH2 c.815C>T on protein function. The variant was shown to mildly affect the normal splicing pattern by causing exon 5 exclusion (Tournier_2008, Lastella_2006, Dominguez-Valentin_2018), however tumors in mutation carriers showed normal MSH2 expression (Ollila_2006). In addition, the variant was shown to be MMR-proficient by the in vitro MMR assay as reported by several independent research groups (Ollila_2006, Ollila_2008, Drost_2011). Taken together these results indicate that this variant does not significantly damage MSH2 protein function. Multiple clinical diagnostic laboratories and an expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments with the expert panel and five other submitters reporting a benign/likely benign outcome. Based on the absence of evidence supporting an actionable outcome in literature spanning over two decades of evolution as outlined above, the variant was re-classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 24, 2017	- -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 04, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jun 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 18, 2020	- -

Lynch syndrome 1

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 24, 2023	This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2020	This variant is associated with the following publications: (PMID: 21120944, 22102614, 16995940, 27449771, 29371908, 10080150, 22949387, 18951462, 17101317, 19690142, 15872200, 20587412, 18561205, 11606497, 18566915, 25637381, 17594722, 22703879, 26951660, 25569433, 27328445, 10422993, 32741062) -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2023	- -

Lynch syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	- -
Benign, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Oct 18, 2018	Multifactorial likelihood analysis posterior probability <0.001 -

Colorectal cancer, non-polyposis

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 23, 2022

- -

MSH2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 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.Ala272Val variant was identified in 1 of 1132 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Hampel 2005). The variant was also identified in dbSNP (ID: rs34136999) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, in ClinVar (classified as benign by Invitae; likely benign by GeneDx, Ambry Genetics, color Genomics; uncertain significance by 5 clinical laboratories), Clinvitae (conflicting interpretations of pathogenicity), MutDB, UMD-LSDB (classified as neutral), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. In UMD the variant was identified with a co-occurring pathogenic MSH2 variant (c.518T>G, p.Leu173Arg), increasing the likelihood that the p.Ala272Val variant does not have clinical significance. The variant was not identified in GeneInsight-COGR, Cosmic, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 77 of 276232 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 23984 chromosomes (freq: 0.0001), Other in 2 of 6438 chromosomes (freq: 0.0003), Latino in 14 of 34346 chromosomes (freq: 0.0004), European Non-Finnish in 49 of 126334 chromosomes (freq: 0.0004), Ashkenazi Jewish in 9 of 10140 chromosomes (freq: 0.001), and South Asian in 1 of 30510 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian, European Finnish, populations. Several functional studies demonstrated this variant resulted in partial exon 5 skipping (Lastella 2006, Tournier 2008) and slightly reduced mismatch binding of the MMR reaction (Ollila 2008). The variant showed no reduction in mismatch repair capability compared with the wild-type MSH2 (Ollila 2006). In addition, the variant was identified with a pathogenic BRCA2 c.9382C>T in a patient diagnosed with ductal carcinoma at 44 years of age (Dominguez-Valentin 2018). The p.Ala272 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.3

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.5

D;D;.;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

D;D;.;D

Sift4G

Uncertain

0.046

D;D;.;T

Polyphen

0.87

P;.;.;D

Vest4

0.87

MVP

0.98

MPC

0.033

ClinPred

0.64

GERP RS

5.0

Varity_R

0.94

gMVP

0.61

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