rs17224360

chr2-47429732-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000251.3(MSH2):c.1077-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,597,360 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 32)
  • Exomes 𝑓: 0.018 (305 hom.)
• Consequence: MSH2 NM_000251.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.3600
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: 1.78

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 2-47429732-T-C is Benign according to our data. Variant chr2-47429732-T-C is described in ClinVar as [Benign]. Clinvar id is 36562.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47429732-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0142 (2157/152306) while in subpopulation AMR AF= 0.0295 (451/15286). AF 95% confidence interval is 0.0273. There are 23 homozygotes in gnomad4. There are 980 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1077-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1077-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2157 AN: 152188 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0295

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0145 AC: 3588 AN: 247944 Hom.: 58 AF XY: 0.0145 AC XY: 1948 AN XY: 134506

Gnomad AFR exome AF: 0.00306

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00455

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0181 AC: 26086 AN: 1445054 Hom.: 305 Cov.: 30 AF XY: 0.0179 AC XY: 12905 AN XY: 719814

Gnomad4 AFR exome AF: 0.00363

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.0391

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00431

Gnomad4 FIN exome AF: 0.00268

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0195

GnomAD4 genome AF: 0.0142 AC: 2157 AN: 152306 Hom.: 23 Cov.: 32 AF XY: 0.0132 AC XY: 980 AN XY: 74474

Gnomad4 AFR AF: 0.00411

Gnomad4 AMR AF: 0.0295

Gnomad4 ASJ AF: 0.0363

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0184 Hom.: 22

Bravo AF: 0.0164

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:24

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2014	- -
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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
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	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Lynch syndrome 1 Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 07, 2015	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 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	clinical testing	Vantari Genetics	Dec 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 18, 2022	- -

Lynch syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH2 c.1077-10T>C variant was identified in at least 4 of 254 proband chromosomes (frequency: 0.016) from individuals with colon cancer and in at least 5 of 226 control chromosomes (frequency: 0.022) (Borresen 1995, Chen-Shtoyerman, Swensen 1997, Tournier 2008). The variant was also identified in the “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, and in UMD (39X as a neutral variant). The c.1077-10T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions; however, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) do not predict a greater than 10% difference in splicing, and an ex vivo splicing assay found no effect of the variant on splicing (Tournier 2008 18561205). The variant was listed in dbSNP (ID: rs17224360) “With non-pathogenic allele”, with a global minor allele frequency of 0.007 (1000 Genomes Project), and a frequency of 0.017 in 60 HapMap individuals, increasing the likelihood that this is a low frequency benign variant in certain populations of origin. In addition, several studies list or describe this variant as a polymorphism or non-pathogenic variant (Borresen 1995, Chen-Shtoyerman, Desai 2000, Jung 2006, Rubio-Del-Campo 2007, Swensen 1997, Tournier 2008). Furthermore, this variant was identified in one individual from our lab with a pathogenic variant co-occurring, increasing the likelihood of this variant having no clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 27, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.36
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.010		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: rs17224360; hg19: chr2-47656871; COSMIC: COSV104575351;