chr2-47462078-G-T

Variant names:

• chr2-47462078-G-T
• rs13019654
• NM_000251.3:c.1387-953G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000233146.7(MSH2):​c.1387-953G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 127,310 control chromosomes in the GnomAD database, including 1,136 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1136 hom., cov: 23)
• Consequence: MSH2 ENST00000233146.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.212
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000233146.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1387-953G>T		intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.1387-953G>T		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1387-953G>T		intron	N/A	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1387-953G>T		intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.1387-953G>T		intron	N/A	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.1387-953G>T		intron	N/A	ENSP00000495455.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 15663 AN: 127240 Hom.: 1137 Cov.: 23

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.0630

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.0788

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.119

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.123 AC: 15668 AN: 127310 Hom.: 1136 Cov.: 23 AF XY: 0.127 AC XY: 7670 AN XY: 60624

African (AFR) AF: 0.0340 AC: 1024 AN: 30150

American (AMR) AF: 0.165 AC: 1983 AN: 12052

Ashkenazi Jewish (ASJ) AF: 0.0630 AC: 206 AN: 3270

East Asian (EAS) AF: 0.268 AC: 1231 AN: 4600

South Asian (SAS) AF: 0.0798 AC: 321 AN: 4022

European-Finnish (FIN) AF: 0.201 AC: 1471 AN: 7302

Middle Eastern (MID) AF: 0.0758 AC: 15 AN: 198

European-Non Finnish (NFE) AF: 0.143 AC: 9060 AN: 63174

Other (OTH) AF: 0.118 AC: 203 AN: 1714

Alfa AF: 0.0671 Hom.: 112

Bravo AF: 0.105

Asia WGS AF: 0.126 AC: 437 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.3
DANN	Benign	0.19
PhyloP100		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs13019654; hg19: chr2-47689217;