rs17218356

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000233146.7(MSH2):​c.1662-9G>A 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 0.00108 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
ENST00000233146.7 splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00006028
2

Clinical Significance

Benign reviewed by expert panel U:2B:16

Conservation

PhyloP100: 0.975
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkuse as main transcriptc.1662-9G>A splice_polypyrimidine_tract_variant, intron_variant ENST00000233146.7 NP_000242.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.1662-9G>A splice_polypyrimidine_tract_variant, intron_variant 1 NM_000251.3 ENSP00000233146 P1P43246-1

Frequencies

GnomAD3 genomes
AF:
0.00461
AC:
700
AN:
151990
Hom.:
3
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.00133
AC:
332
AN:
249892
Hom.:
2
AF XY:
0.00110
AC XY:
149
AN XY:
135284
show subpopulations
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 SAS exome
AF:
0.0000986
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
show subpopulations
Gnomad4 AFR exome
AF:
0.0168
Gnomad4 AMR exome
AF:
0.00163
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000523
Gnomad4 SAS exome
AF:
0.0000873
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000125
Gnomad4 OTH exome
AF:
0.00158
GnomAD4 genome
AF:
0.00460
AC:
700
AN:
152108
Hom.:
3
Cov.:
32
AF XY:
0.00438
AC XY:
326
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0145
Gnomad4 AMR
AF:
0.00406
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00948
Alfa
AF:
0.00134
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:2Benign:16
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:5
Uncertain significance, no assertion criteria providedresearchMayo Clinic Laboratories, Mayo Clinic-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 17, 2017- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 28, 2018- -
Lynch syndrome 1 Uncertain:1Benign:3
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical CenterSep 07, 2017- -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 18, 2014This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 18, 2015- -
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioNov 09, 2021- -
Carcinoma of colon Benign:1
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Lynch syndrome Benign:1
Benign, reviewed by expert panelresearchInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Sep 05, 2013Multifactorial likelihood analysis posterior probability <0.001 -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
CADD
Benign
13
DANN
Benign
0.59

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs17218356; hg19: chr2-47698095; COSMIC: COSV104575435; API