chr2-47408528-G-A

Position:

• chr2-47408528-G-A

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.339G>A​(p.Lys113=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,609,290 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0052 (31 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:30
• Conservation: PhyloP100: 0.932

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=-0.52).
• BP6: Variant 2-47408528-G-A is Benign according to our data. Variant chr2-47408528-G-A is described in ClinVar as [Benign]. Clinvar id is 36576.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47408528-G-A is described in Lovd as [Benign]. Variant chr2-47408528-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.932 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00308 (468/152106) while in subpopulation NFE AF= 0.00515 (350/67994). AF 95% confidence interval is 0.0047. There are 0 homozygotes in gnomad4. There are 198 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.339G>A	p.Lys113=	synonymous_variant	2/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.339G>A	p.Lys113=	synonymous_variant	2/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 467 AN: 151988 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00294 AC: 738 AN: 251286 Hom.: 3 AF XY: 0.00297 AC XY: 403 AN XY: 135820

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00488

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00520 AC: 7572 AN: 1457184 Hom.: 31 Cov.: 31 AF XY: 0.00500 AC XY: 3624 AN XY: 725212

Gnomad4 AFR exome AF: 0.000749

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000975

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00624

Gnomad4 OTH exome AF: 0.00543

GnomAD4 genome AF: 0.00308 AC: 468 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.00266 AC XY: 198 AN XY: 74356

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00515

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00514 Hom.: 3

Bravo AF: 0.00338

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00535

EpiControl AF: 0.00492

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:30

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:12

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	Sep 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 17, 2019	- -

Lynch syndrome 1 Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 08, 2015	- -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 16, 2020	- -
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	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 25, 2023	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 11, 2017	- -

Lynch syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 01, 2012	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Synonymous variant with no effect on splicing, MAF 0.01-1% & >3 MSS/MSH2 IHC normal CRC tumours. Multifactorial likelihood analysis posterior probability <0.001 -
Benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH2 p.Lys113Lys variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant was identified in the literature in 5 of 744 proband chromosomes (frequency 0.007) from individuals with colon cancer and was absent in 180 control chromosomes evaluated from these studies (Liu 1998, Palicio 2002, Pastrello 2011, Tournier 2008). The variant was also identified in dbSNP (ID: rs35898375) “With probable-non-pathogenic allele”, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “MMR Gene Unclassified Variants Database” and UMD (11X as a neutral variant). Within the UMD listing, the variant is listed to co-occur with a known pathogenic mutation in MSH2 (c.1058del, p.Lys353ArgfsX4), increasing the likelihood that this variant does not have clinical importance. Pastrello (2011) found this variant in three families that were Amsterdam-like or met Amsterdam I criteria; in all three cases the variant was found to co-occur with a pathogenic mutation in either MLH1 or MSH2. In one of the three families, the variant was determined to be in trans with a pathogenic MSH2 mutation, and the tumour showed loss of heterozygosity of the p.Lys113Lys variant allele, further increasing the likelihood of the variant not having clinical importance. In addition, one functional assay demonstrated no effect of this variant on splicing, which was concordant with analysis of patient RNA (Tournier 2008). Finally, the variant was reported in the 1000 Genomes project with a frequency of 0.002 and in the ClinSeq project with a frequency of 0.007, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 30, 2023

- -

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
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.8
DANN	Benign	0.39

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: rs35898375; hg19: chr2-47635667; COSMIC: COSV104575383;