rs61756468

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000251.3(MSH2):c.1886A>G(p.Gln629Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,614,156 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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: 0.00038 ( 4 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:18O:1

Conservation

PhyloP100: 1.26

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 -18 ACMG points.

PM1

In a region_of_interest Interaction with EXO1 (size 70) in uniprot entity MSH2_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in NM_000251.3

BP4

Computational evidence support a benign effect (MetaRNN=0.014180899).

BP6

Variant 2-47475151-A-G is Benign according to our data. Variant chr2-47475151-A-G is described in ClinVar as [Benign]. Clinvar id is 90812.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475151-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000545 (83/152284) while in subpopulation EAS AF= 0.0145 (75/5180). AF 95% confidence interval is 0.0118. There are 1 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1886A>G	p.Gln629Arg	missense_variant	12/16	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.1886A>G	p.Gln629Arg	missense_variant	12/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152166

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:

0.0144

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00120

AC:

303

AN:

251464

Hom.:

AF XY:

0.00112

AC XY:

152

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0158

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000383

AC:

560

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

265

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0130

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.000545

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0145

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000280

Hom.:

Bravo

AF:

0.000703

ExAC

AF:

0.00129

AC:

157

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:18Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 02, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 03, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Lynch syndrome 1

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2016	Variant summary: The MSH2 c.1886A>G (p.Gln629Arg) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 159/123118 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0174486 (151/8654). This frequency is about 31 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. This variant has also been reported in colorectal patients or HNPCC-related cancer without strong evidence for pathogenicity. In a family, while affected proband carried the variant, another affected cousin did not carry the variant, possibly suggesting that it did not co-segregate with disease in the family (Woo_2014). Multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2018	This variant is associated with the following publications: (PMID: 24933000, 22995991, 22283331, 22949387, 29506494, 27487738, 15365995, 21155023, 22290698, 20965939, 23760103, 24728327, 12132870, 26332594, 25985138, 24078570, 29642919, 15996210, 16929514, 18257912, 18383312, 18636359, 18726168, 24396821, 28580595) -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 07, 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.Gln629Arg variant was identified in 8 of 882 proband chromosomes (frequency: 0.009) from individuals or families with colon cancer, gastric cancer, and hepatocellular carcinoma (Jin 2008, Lee 2005, Lim 2010, Shin 2004, Wang 2006, Yano 2007, Yap 2009, Zhang 2006). Yuan (2004) also found the variant in 7 of 200 chromosomes in unaffected individuals (freq 0.035), and therefore classified the variant as a polymorphism. The variant was also identified in dbSNP (ID: rs61756468) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (as benign, reviewed by an expert panel), Clinvitae (as benign), Cosmic, Insight Colon Cancer Gene Variant Database (reported 19x as benign), Zhejiang Colon Cancer Database (reported 6x), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in MutDB, UMD-LSDB, MMR Gene Unclassified Variants Database. The variant was identified in control databases in 317 of 277184 chromosomes at a frequency of 0.0011 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 304 (1 homozygous) of 18870 chromosomes (freq: 0.01611), Other in 2 of 6464 chromosomes (freq: 0.000309), European (Non-Finnish) in 1 of 126690 chromosomes (freq: 0.000008), European (Finnish) in 3 of 25786 chromosomes (freq: 0.000116), and South Asian in 7 of 30782 chromosomes (freq: 0.000227), while the variant was not observed in the African, Latino, or Ashkenazi Jewish populations. The p.Gln629 residue is not conserved in mammals and 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. 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.45

T;.;.;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.72

T;T;T;T

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.1

L;.;.;.

MutationTaster

Benign

0.85

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

N;N;.;N

REVEL

Uncertain

0.51

Sift

Benign

0.32

T;T;.;T

Sift4G

Benign

0.12

T;T;.;T

Polyphen

0.0

B;.;.;B

Vest4

0.30

MVP

1.0

MPC

0.0064

ClinPred

0.0094

GERP RS

2.3

Varity_R

0.12

gMVP

0.57

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