NM_000251.3:c.705delA

Variant names:

• chr2-47412469-CA-C
• rs281864944
• NM_000251.3:c.705delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.705delA​(p.Asp236ThrfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 0.212
• Publications: 6 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47412469-CA-C is Pathogenic according to our data. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CA-C is described in CliVar as Pathogenic. Clinvar id is 91183.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.705delA	p.Asp236ThrfsTer10	frameshift_variant	Exon 4 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.705delA	p.Asp236ThrfsTer10	frameshift_variant	Exon 4 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Jul 27, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Coding sequence variation resulting in a stop codon -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 25, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.705delA pathogenic mutation, located in coding exon 4 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 705, causing a translational frameshift with a predicted alternate stop codon (p.D236Tfs*10). This specific variant has not been reported in the literature; however, another alteration, MSH2 c.702delA, with the same predicted alternate stop codon has been identified in a Druze HNPCC family. The family consisted of 10 members in 4 generations affected with either colorectal cancer (mean age at diagnosis was 46.5 years), gastric cancer, or endometrial cancer (Zidan J et al. Fam. Cancer, 2008;7:135-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs281864944; hg19: chr2-47639608;