2-47470969-T-C

Position:

chr2-47470969-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000251.3(MSH2):c.1666T>C(p.Leu556=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,469,858 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0046 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 36 hom. )

Consequence

MSH2
NM_000251.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:28

Conservation

PhyloP100: 1.07

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 2-47470969-T-C is Benign according to our data. Variant chr2-47470969-T-C is described in ClinVar as [Benign]. Clinvar id is 36568.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47470969-T-C is described in Lovd as [Benign]. Variant chr2-47470969-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.08 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00456 (694/152302) while in subpopulation NFE AF= 0.00651 (443/68018). AF 95% confidence interval is 0.00601. There are 2 homozygotes in gnomad4. There are 330 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1666T>C	p.Leu556=	synonymous_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.1666T>C	p.Leu556=	synonymous_variant	11/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.00456

AC:

694

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00524

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00490

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00651

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00428

AC:

1071

AN:

249980

Hom.:

AF XY:

0.00445

AC XY:

602

AN XY:

135192

show subpopulations

Gnomad AFR exome

AF:

0.00156

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000925

Gnomad FIN exome

AF:

0.00365

Gnomad NFE exome

AF:

0.00700

Gnomad OTH exome

AF:

0.00525

GnomAD4 exome

AF:

0.00544

AC:

7168

AN:

1317556

Hom.:

Cov.:

AF XY:

0.00535

AC XY:

3546

AN XY:

663382

show subpopulations

Gnomad4 AFR exome

AF:

0.000848

Gnomad4 AMR exome

AF:

0.00223

Gnomad4 ASJ exome

AF:

0.00345

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00111

Gnomad4 FIN exome

AF:

0.00415

Gnomad4 NFE exome

AF:

0.00644

Gnomad4 OTH exome

AF:

0.00535

GnomAD4 genome

AF:

0.00456

AC:

694

AN:

152302

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

330

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00523

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00490

Gnomad4 NFE

AF:

0.00651

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00594

Hom.:

Bravo

AF:

0.00433

EpiCase

AF:

0.00742

EpiControl

AF:

0.00694

ClinVar

Significance: Benign

Submissions summary: Benign:28

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:11

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 07, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 18, 2021	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2013	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. -

Lynch syndrome 1

Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 10, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:5

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	May 27, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 27, 2023	- -

Lynch syndrome

Benign:2

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Multifactorial likelihood analysis posterior probability <0.001 -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 22, 2013	- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Leu556Leu variant is not expected to have clinical significance because it does not alter an amino acid residue. It has been reported in the literature in 11/5116 proband chromosomes of individuals with either HNPCC or like-HNPCC. It was also identified in 1/340 control chromosomes. While some of the patients met either the strict Bethesda or Amsterdam criterias, others met only one of the guidelines or were missing some of the parameters within a particular criteria evaluated. (Auclair_2006, Hendriks_2003, Pastrello_2011, Scartozzi_2002, Tournier_2008, Wijnen_1995, Wehner_1997, Mangold_2005, Scott_2001). Of the one study where IHC results were available, MSH2 staining was normal in the patient with the variant (Hendriks_2003). Microsatellite status results were inconsistent with one paper citing low MSI in the variant positive tumor (Hendriks_2003), while another tumor exhibited high MSI (Pastrello_2011). The variant was also reported in the UMD (x23), InSiGHT Colon Cancer and Exome Server databases. The variant is listed in the dbSNP database as coming from a "clinical source" (ID#: rs61756466) with a MAF score of 0.003 (1000 Genomes), increasing the likelihood that this is a low frequency benign variant. Functional studies examining the effect of the variant on splicing reported that no aberrant splicing was detected (Auclair_2006, Tournier_2008). The identification of this variant in the presence of a second pathogenic variant increases the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant is 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

May 25, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

MSH2: BP4, BP7, BS2 -

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 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.3

DANN

Benign

0.69

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