2-47476515-A-G

Position:

• chr2-47476515-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000251.3(MSH2):​c.2154A>G​(p.Gln718Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,614,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:19
• Conservation: PhyloP100: 0.883

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-47476515-A-G is Benign according to our data. Variant chr2-47476515-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 90910.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476515-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.883 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2154A>G	p.Gln718Gln	synonymous_variant	13/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2154A>G	p.Gln718Gln	synonymous_variant	13/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251484 Hom.: 0 AF XY: 0.000235 AC XY: 32 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000299 AC: 437 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.000307 AC XY: 223 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000374

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74492

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000732 Hom.: 0

Bravo AF: 0.000185

EpiCase AF: 0.000654

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:19

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MSH2: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH2 p.Gln718= variant was identified in 2 of 3494 proband chromosomes (frequency: 0.0006) from individuals or families with HNPCC (Mangold 2005, Renkonen 2003). The variant was also identified in dbSNP (ID: rs63750810) as "With other allele”, ClinVar (classified as benign by Invitae, GeneDx, and two other submitters; and as likely benign by InSiGHT expert panel, Prevention Genetics and Ambry Genetics), and UMD-LSDB (1x as neutral). The variant was identified in control databases in 90 of 277216 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 1 of 34420 chromosomes (freq: 0.00003), European in 85 of 126710 chromosomes (freq: 0.0007), Ashkenazi Jewish in 2 of 10152 chromosomes (freq: 0.0002), and East Asian in 1 of 18868 chromosomes (freq: 0.00005), while the variant was not observed in the African, Finnish, or South Asian populations. This variant was identified in a patient with an unspecified co-occurring, pathogenic variant (Mangold 2015). The p.Gln718= 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. However, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing. 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 likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 22, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2014	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. -
Likely 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2018	Variant summary: MSH2 c.2154A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00032 in 277216 control chromosomes, predominantly at a frequency of 0.00067 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.18 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2154A>G has been reported in the literature in individuals affected with Lynch Syndrome (Mangold_2005, Renkonen_2003). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additonally, one publication reports the variant to co-occur with a pathogenic variant, further evidence for the benign nature of this variant (Mangold_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 30, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 2014	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	curation	Sema4, Sema4	Feb 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 12, 2023	- -

Lynch syndrome 1 Uncertain:1 Benign:2

Likely 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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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 12, 2022

- -

Lynch syndrome Benign:1

Likely benign, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Oct 18, 2018

Synonymous substitution with no effect on splicing tested with NMD inhibitor. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.9
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs63750810; hg19: chr2-47703654; COSMIC: COSV51877783;