rs6741393

Variant names:

• chr2-47462781-G-A
• rs6741393
• NM_000251.3:c.1387-250G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47462781-G-A
• chr2-47462781-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000251.3(MSH2):​c.1387-250G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 152,120 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.040 (137 hom., cov: 32)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.615
• Publications: 5 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: ClinGen, Orphanet, G2P
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 2-47462781-G-A is Benign according to our data. Variant chr2-47462781-G-A is described in ClinVar as Benign. ClinVar VariationId is 90646.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1387-250G>A		intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1387-250G>A		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1387-250G>A		intron	N/A	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1387-250G>A		intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1387-250G>A		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1438-250G>A		intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0398 AC: 6045 AN: 152002 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0582

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.0586

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0325

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

GnomAD4 genome AF: 0.0398 AC: 6052 AN: 152120 Hom.: 137 Cov.: 32 AF XY: 0.0398 AC XY: 2958 AN XY: 74364

African (AFR) AF: 0.0582 AC: 2416 AN: 41498

American (AMR) AF: 0.0215 AC: 329 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00810 AC: 39 AN: 4816

European-Finnish (FIN) AF: 0.0586 AC: 619 AN: 10558

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0362 AC: 2463 AN: 67994

Other (OTH) AF: 0.0317 AC: 67 AN: 2112

Alfa AF: 0.0334 Hom.: 148

Bravo AF: 0.0382

Asia WGS AF: 0.00985 AC: 34 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Lynch syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.10
DANN	Benign	0.15
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6741393; hg19: chr2-47689920;