chr2-47470993-A-G

Position:

chr2-47470993-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000251.3(MSH2):c.1690A>G(p.Thr564Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000588 in 1,564,040 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 Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T564N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:15

Conservation

PhyloP100: 2.41

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024828196).

BP6

Variant 2-47470993-A-G is Benign according to our data. Variant chr2-47470993-A-G is described in ClinVar as [Benign]. Clinvar id is 90750.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47470993-A-G is described in Lovd as [Benign]. Variant chr2-47470993-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1690A>G	p.Thr564Ala	missense_variant	11/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.1690A>G	p.Thr564Ala	missense_variant	11/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152218

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:

0.00269

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000232

AC:

AN:

250388

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00310

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000545

AC:

AN:

1411704

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

705514

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00145

Gnomad4 SAS exome

AF:

0.0000471

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000187

Gnomad4 OTH exome

AF:

0.000205

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000982

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.000867

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 02, 2017	Variant summary: The MSH2 c.1690A>G (p.Thr564Ala) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index). This variant was found in 22/120830 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.002547 (22/8638). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant was found in several studies assessing colorectal cancer patients with normal IHC and microsatellite stable tumors; however no strong evidence for pathogenicity were present. Furthermore, in one family the variant did not co-segregate with the disease, and the cause of cancer in this family was attributed to a pathogenic variant in the APC gene, further supporting a neutral outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Considering all evidence, the variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2020	This variant is associated with the following publications: (PMID: 22290698, 15996210, 24362816, 12200596, 18726168, 24735542, 17192056, 25980754, 24710284, 26900293, 29506494) -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 14, 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	Color Diagnostics, LLC DBA Color Health	Nov 03, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 23, 2021	- -

Lynch syndrome 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 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: This variant has been seen in 0.25% of East Asian chrs (0.31% in gnomAD - too high for disease frequency). It is classified in ClinVar with 3 stars as benign by an expert panel (InSiGHT) and Invitae. It has been reported in 3 papers: in one it did not segregate in the family with disease, in one it was predicted to be not pathogenic, and one where MSH2 expression was retained. Rabbit also has an Alanine at this position. -

MSH2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

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). -

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

Oct 06, 2022

- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Thr564Ala variant was identified in 8 of 468 proband chromosomes (frequency: 0.02) from Chinese and Taiwanese individuals or families with HNPCC/suspected HNPCC related CRC (Chang_2016_26900293, Lee_2005_15996210, Yap_2009_18726168). In a 4 generation Han Chinese family affected with polyposis, sequencing of 5 genes related to HNPCC/FAP found the variant to co-occur with a truncating APC variant (c.694C>), and the variant was found in both affected and unaffected members (Zhang_2014_24735542). Two bioinformatics prediction models pathogenic-or-not mismatch repair (PONMMR), and multivariate analysis of protein polymorphismsâ€šÃ„Ã¬mismatch repair (MAPP-MMR) assessed the variant as neutral (Ali_2012_22290698, Chao_2008_18383312). The variant was also identified in dbSNP (ID: rs55778204) â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (classified benign, reviewed by an expert panel (2013); submitters: benign by InSIGHT, and likely benign by Invitae, GeneDx, Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (2x), Insight Colon Cancer Gene Variant Database (13x as class 1), Zhejiang Colon Cancer Database (2x), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (14x), and was not identified in GeneInsight-COGR, Cosmic, MutDB, or UMD-LSDB. The variant was identified in control databases in 59 of 276412 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 59 of 18860 chromosomes (freq: 0.003), while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr564 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 the variant Ala impacting the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 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 this variant meets our laboratory's criteria to be classified as benign. -

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

Invitae

Feb 01, 2024

- -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.35

T;.;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

T;T;T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.025

T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.1

L;.;.;.

MutationTaster

Benign

0.86

D;D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.73

N;N;.;N

REVEL

Uncertain

0.49

Sift

Benign

0.81

T;T;.;T

Sift4G

Benign

0.78

T;T;.;T

Polyphen

0.0

B;.;.;B

Vest4

0.77

MutPred

0.81

Loss of phosphorylation at T564 (P = 0.0335);.;Loss of phosphorylation at T564 (P = 0.0335);Loss of phosphorylation at T564 (P = 0.0335);

MVP

0.99

MPC

0.0066

ClinPred

0.049

GERP RS

3.3

Varity_R

0.066

gMVP

0.32

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