chr2-47475050-CAAT-C

Variant names:

• chr2-47475050-CAAT-C
• rs63749831
• NM_000251.3:c.1786_1788delAAT

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000251.3(MSH2):​c.1786_1788delAAT​(p.Asn596del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000919714: At least one publication reports experimental evidence evaluating an impact on protein function (Heinen_2003, Drost_2011, Heinen_2002)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:19 O:1
• Conservation: PhyloP100: 8.51
• Publications: 33 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

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000919714: At least one publication reports experimental evidence evaluating an impact on protein function (Heinen_2003, Drost_2011, Heinen_2002).; SCV004827333: Functional studies have found the variant protein to be defective in DNA mismatch repair, ATP binding and ATPase assays (PMID: 12124176, 22102614).; SCV000684976: Functional studies have found the variant protein to be defective in DNA mismatch repair, ATP binding and ATPase assays (PMID: 12124176, 22102614).; SCV000211230: Published functional studies support a damaging effect: reduced DNA mispair recognition, binding, and ATP hydrolysis, and causing deficient mismatch repair activity (Heinen 2002, Drost 2012).; SCV001469802: in vitro studies indicated that the variant results in defective DNA repair, ATP binding and ATPase assay (PMIDs: 12124176 (2002), 22102614 (2012)).; SCV000255273: Experimental studies have shown that this variant affects MSH2 function (PMID: 12124176, 22102614).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 35 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000251.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-47475050-CAAT-C is Pathogenic according to our data. Variant chr2-47475050-CAAT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1757.Status of the report is reviewed_by_expert_panel, 3 stars.

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.1786_1788delAAT	p.Asn596del	conservative_inframe_deletion	Exon 12 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1786_1788delAAT	p.Asn596del	conservative_inframe_deletion	Exon 12 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.1786_1788delAAT	p.Asn596del	conservative_inframe_deletion	Exon 12 of 18	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1786_1788delAAT	p.Asn596del	conservative_inframe_deletion	Exon 12 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1786_1788delAAT	p.Asn596del	conservative_inframe_deletion	Exon 12 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1837_1839delAAT	p.Asn613del	conservative_inframe_deletion	Exon 13 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251458 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461262 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726978

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111474

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Lynch syndrome 1 (6)
3	-	-	Lynch syndrome (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Carcinoma of colon (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	MSH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.5
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs63749831; hg19: chr2-47702189;