rs528263777

chr2-47408461-ATCT-Achr2-47408461-A-ATCT

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PM4_Supporting BP6_Very_Strong

The NM_000251.3(MSH2):c.279_281del(p.Leu94del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000158 in 1,612,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: MSH2 NM_000251.3 inframe_deletion
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: 6.94

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 -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000251.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-47408461-ATCT-A is Benign according to our data. Variant chr2-47408461-ATCT-A is described in ClinVar as [Benign]. Clinvar id is 91050.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47408461-ATCT-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.279_281del	p.Leu94del	inframe_deletion	2/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.279_281del	p.Leu94del	inframe_deletion	2/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.000435 AC: 66 AN: 151878 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251238 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135794

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1460914 Hom.: 0 AF XY: 0.000132 AC XY: 96 AN XY: 726800

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000963

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000441 AC: 67 AN: 151996 Hom.: 0 Cov.: 31 AF XY: 0.000377 AC XY: 28 AN XY: 74280

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000404

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2021	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 04, 2024	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2020	This variant is associated with the following publications: (PMID: 12373605, 10495924, 15872200, 11546830, 11879922, 25111426, 18561205, 23729658) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 11, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 23, 2019	Variant summary: MSH2 c.279_281delTCT (p.Leu94del) results in an in-frame deletion that is predicted to remove one of three consecutive Leucine from the encoded protein. 5/5 computational tools predict no significant impact on normal splicing, which was confirmed by one ex vivo splicing assay (Tournier_2008). The variant allele was found at a frequency of 0.00018 in 282552 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-folds higher than 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 African or African-American origin. c.279_281delTCT has been reported in the literature in individuals affected with CRC, HNPCC, and endometrial cancers (DeRycke_2017, Dymerska_2010, Geurts-Giele_2014, Gille_2002, Hampel_2005, Kurzawski_2006, Liu_2001) including one family that showed the variant to no segregate with disease (Liu_2001). Co-occurrence with other pathogenic variant has been reported (MSH2 c.638_639delTG, p.Leu213GlnfsX18), providing supporting evidence for a benign role. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) and an reputable database (InSiGHT) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Lynch syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability <0.001 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

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: rs267607919; hg19: chr2-47635600;