2-47470969-T-C

Position:

• chr2-47470969-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign reviewed by expert panel B:29
• Conservation: PhyloP100: 1.07

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]

ACMG classification

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	Protein	UniProt
MSH2	NM_000251.3	c.1666T>C	p.Leu556=	synonymous_variant	11/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1666T>C	p.Leu556=	synonymous_variant	11/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152184 Hom.: 2 Cov.: 32

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.: 4 AF XY: 0.00445 AC XY: 602 AN XY: 135192

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.: 36 Cov.: 20 AF XY: 0.00535 AC XY: 3546 AN XY: 663382

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.: 2 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74474

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.: 1

Bravo AF: 0.00433

EpiCase AF: 0.00742

EpiControl AF: 0.00694

ClinVar

Significance: Benign

Submissions summary: Benign:29

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:11

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

Lynch syndrome 1 Benign:5

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	- -
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	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
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	- -
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, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 22, 2013	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Multifactorial likelihood analysis posterior probability <0.001 -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MSH2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

Other links and lift over

dbSNP: rs61756466; hg19: chr2-47698108; COSMIC: COSV51882866;