chr2-47470956-G-A

Variant names:

• chr2-47470956-G-A
• rs17218356
• NM_000251.3:c.1662-9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000251.3(MSH2):​c.1662-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,341,742 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (8 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Scores: Splicing: ADA: 0.00006028
• Clinical Significance: Benign reviewed by expert panel U:2 B:18
• Conservation: PhyloP100: 0.975

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-47470956-G-A is Benign according to our data. Variant chr2-47470956-G-A is described in ClinVar as [Benign]. Clinvar id is 90730.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47470956-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0046 (700/152108) while in subpopulation AFR AF = 0.0145 (603/41488). AF 95% confidence interval is 0.0136. There are 3 homozygotes in GnomAd4. There are 326 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1662-9G>A		intron_variant	Intron 10 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1662-9G>A		intron_variant	Intron 10 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 700 AN: 151990 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00133 AC: 332 AN: 249892 AF XY: 0.00110

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000634 AC: 754 AN: 1189634 Hom.: 8 Cov.: 17 AF XY: 0.000580 AC XY: 351 AN XY: 605536

Gnomad4 AFR exome AF: 0.0168 AC: 473 AN: 28142

Gnomad4 AMR exome AF: 0.00163 AC: 72 AN: 44254

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24418

Gnomad4 EAS exome AF: 0.0000523 AC: 2 AN: 38216

Gnomad4 SAS exome AF: 0.0000873 AC: 7 AN: 80182

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53118

Gnomad4 NFE exome AF: 0.000125 AC: 108 AN: 865432

Gnomad4 Remaining exome AF: 0.00158 AC: 81 AN: 51132

GnomAD4 genome AF: 0.00460 AC: 700 AN: 152108 Hom.: 3 Cov.: 32 AF XY: 0.00438 AC XY: 326 AN XY: 74354

Gnomad4 AFR AF: 0.0145 AC: 0.0145343 AN: 0.0145343

Gnomad4 AMR AF: 0.00406 AC: 0.00405812 AN: 0.00405812

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.000207814 AN: 0.000207814

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000206 AC: 0.000205901 AN: 0.000205901

Gnomad4 OTH AF: 0.00948 AC: 0.00947867 AN: 0.00947867

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00544

Asia WGS AF: 0.00145 AC: 5 AN: 3474

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:18

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:5

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 1 Uncertain:1 Benign:4

Sep 07, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 10, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 18, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.1662-9G>A variant was identified in 3 of 584 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer (Montera 2000, Farrington 1998, Thompson 2013). The variant was also identified in dbSNP (ID: rs17218356) as “With other allele”, ClinVar (classified as benign by an InSiGHT expert panel (2013) and five other submitters; as likely benign by 2 submitters; and as uncertain significance by 2 submitters). The variant was not identified in UMD-LSDB. The variant was also identified in control databases in 465 (4 homozygous) of 276212 chromosomes at a frequency of 0.002, 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: African in 386 (4 homozygous) of 23980 chromosomes (freq: 0.02), Other in 14 of 6450 chromosomes (freq: 0.002), Latino in 38 of 34372 chromosomes (freq: 0.001), European Non-Finnish in 22 of 126108 chromosomes (freq: 0.0002), East Asian in 2 of 18846 chromosomes (freq: 0.0001), and South Asian in 3 of 30556 chromosomes (freq: 0.0001), while it was not observed in the Ashkenazi Jewish or European Finnish populations. The c.1662-9G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions, although positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Furthermore, in vitro splicing analysis performed by Thompson (2013) determined the splicing of this allele to be similar to wild type. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Breast and/or ovarian cancer Benign:1

Nov 09, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability <0.001 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.59
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000060
dbscSNV1_RF	Benign	0.010
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: rs17218356; hg19: chr2-47698095;