2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAA

Position:

• chr2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000251.3(MSH2):​c.942+29delA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.52 (7247 hom., cov: 0)
  • Exomes 𝑓: 0.19 (2857 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 2.32

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 -9 ACMG points.

• BP6: Variant 2-47414420-TA-T is Benign according to our data. Variant chr2-47414420-TA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374958.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr2-47414420-TA-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.942+29delA		intron_variant		ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.942+29delA		intron_variant		1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 32386 AN: 61918 Hom.: 7242 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.567

GnomAD3 exomes AF: 0.0792 AC: 4150 AN: 52420 Hom.: 14 AF XY: 0.0737 AC XY: 2070 AN XY: 28096

Gnomad AFR exome AF: 0.0689

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.0620

Gnomad EAS exome AF: 0.105

Gnomad SAS exome AF: 0.0844

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0627

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.186 AC: 174831 AN: 937556 Hom.: 2857 Cov.: 0 AF XY: 0.183 AC XY: 84884 AN XY: 463688

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.199

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.523 AC: 32391 AN: 61922 Hom.: 7247 Cov.: 0 AF XY: 0.519 AC XY: 14222 AN XY: 27428

Gnomad4 AFR AF: 0.378

Gnomad4 AMR AF: 0.622

Gnomad4 ASJ AF: 0.604

Gnomad4 EAS AF: 0.605

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.593

Gnomad4 NFE AF: 0.585

Gnomad4 OTH AF: 0.569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Lynch syndrome 1 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Mismatch repair cancer syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jun 28, 2018

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 11, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2019

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2020

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Sep 25, 2021

- -

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: rs11309117; hg19: chr2-47641559;