chr2-47429833-C-T

Position:

chr2-47429833-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000251.3(MSH2):c.1168C>T(p.Leu390Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00074 in 1,614,116 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00055 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 15 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:15O:1

Conservation

PhyloP100: 1.61

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011555076).

BP6

Variant 2-47429833-C-T is Benign according to our data. Variant chr2-47429833-C-T is described in ClinVar as [Benign]. Clinvar id is 41641.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47429833-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000552 (84/152272) while in subpopulation EAS AF= 0.0156 (81/5178). AF 95% confidence interval is 0.0129. There are 1 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1168C>T	p.Leu390Phe	missense_variant	7/16	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.1168C>T	p.Leu390Phe	missense_variant	7/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152154

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:

0.0156

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00155

AC:

389

AN:

251454

Hom.:

AF XY:

0.00146

AC XY:

199

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0200

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000759

AC:

1110

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000749

AC XY:

545

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0260

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000552

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0156

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000413

Hom.:

Bravo

AF:

0.000824

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00166

AC:

201

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:15Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2.1% in East Asian population with 2 homozygotes. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2022	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2018	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. -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 09, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 11, 2014	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:1Benign:1

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2016	Variant summary: The c.1168C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is found in 229/123604 control chromosomes (2 homozygotes) at a frequency of 0.0018527. The frequency of this variant in East Asian control population is 0.0217, which is about 38 times of the maximal expected frequency of a pathogenic allele (0.0005683), suggesting this variant is benign. This variant has been reported in a large number of patients with LS or endometrial cancer. Two co-occurrences with a pathogenic variant (MLH1, c.2157dup, p.Val720Cysfs*3 and MSH2 c.196-187dupG, respectively) were reported, along with a reported lack of co-segregation with the disease (Okamura_1998). Multiple functional studies showed that MSH2 p.L390F has similar activity to wild-type MSH2. In addition, multiple clinical laboratories/reputable databases classified this variant as benign. Taken together, this variant was classified as benign. -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 29, 2021

- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Leu390Phe variant was identified in 12 of 952 proband chromosomes (frequency: 0.013) from individuals or families with colorectal cancer (Jin 2008, Lee 2005, Wei 2011, Yap 2009, Zhang 2006) and was present in 1 of 220 control chromosomes (frequency: 0.005) from healthy individuals (Zhang 2006). The variant was also identified in dbSNP (ID: rs17224367) as With other allele, ClinVar (classified as benign by InSight, Emory Genetics, Ambry Genetics, Invitae; classified as likely benign by GeneDx, Illumina, LMMPHCPM; classified as uncertain significance by BLDSNIH), Clinvitae (classified as benign by ClinVar, Invitae, EmvClass; classified as uncertain significance by ClinVar), MutDB , UMD-LSDB (2X classified as neutral), Insight Colon Cancer Gene Variant Database (44X classified as class 1), Zhejiang Colon Cancer Database (7X ), Mismatch Repair Genes Variant Database, databases. The variant was not identified in Cosmic, Insight Hereditary Tumors Database, databases. In UMD the variant was identified with a co-occurring pathogenic MLH1 variant (c.304G>A (p.Glu102Lys)), increasing the likelihood that the p.Leu390Phe variant does not have clinical significance. The variant was identified in control databases in 402(4 homozygous) of 277162 chromosomes at a frequency of 0.00145 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu390 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the DNA mismatch repair protein MutS, core DNA mismatch repair protein, MSH2 functional domains, increasing the likelihood that it may have clinical significance. Functional study of MSH2 on the corresponding yeast allele L402 demonstrated no reduction in steady-state levels of MSH2 and positive interaction with all MSH2 partners (Gammie 2007). The variant was also found co-occurring with pathogenic mutation MLH1 variant c.2157dupT (Wei 2011). However, study by Fan (2005) provides strong molecular epidemiologic, structural, bioinformatic, and functional evidence that MSH2 c.1168C>T (p.Leu390Phe) underlies a newly identified phenotype relevant to young sporadic CRC or GC. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Lynch syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Lynch syndrome

Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability <0.001 -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

D;D;D;D

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.6

M;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.6

D;D;.;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.011

D;D;.;D

Sift4G

Uncertain

0.037

D;D;.;D

Polyphen

0.15

B;.;.;B

Vest4

0.50

MVP

0.91

MPC

0.0094

ClinPred

0.11

GERP RS

4.6

Varity_R

0.66

gMVP

0.58

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