2-47412448-GAA-GA

Position:

• chr2-47412448-GAA-GA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.687del​(p.Ala230LeufsTer16) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. RKKA227RKK?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 0.580

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 2-47412448-GA-G is Pathogenic according to our data. Variant chr2-47412448-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 91177.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412448-GA-G is described in Lovd as [Pathogenic]. Variant chr2-47412448-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.687del	p.Ala230LeufsTer16	frameshift_variant	4/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.687del	p.Ala230LeufsTer16	frameshift_variant	4/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457994 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725586

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 27, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 20, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2019	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 23741719, 15926618, 10480359, 15849733, 10404063, 26648449, 27300758, 24933100, 16206289, 30521064, 31118792, 32885271) -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2, p.Ala230LeufsX16 variant was identified in 2 of 3660 proband chromosomes (frequency: 0.001) from individuals or families of Austrian and German ethnicity with Lynch Syndrome, and was not identified in 100 control chromosomes from healthy individuals (Mangold 2005, Wolf 2005). The variant was also identified in dbSNP (ID: rs63749897) as “With Pathogenic allele”. The variant was further identified in the ClinVar and Clinvitae databases, listed by InSIGHT and the Mayo Clinic Genetic Testing Laboratories as pathogenic; in the COSMIC database, 1x with a histology of Adenocarcinoma with a confirmed somatic mutation; in the InSiGHT Colon Cancer Gene Variant database (LOVD), 11x as Class 5; and in the UMD database 2x with a causal classification. The variant was also identified by our laboratory in 1 individual with endometrial cancer. This variant was not identified in the 1000 Genomes Project, in the NHLBI GO Exome Sequencing Project, and in the Exome Aggregation Consortium (Mar 14, 2016) databases nor was it identified in the MutDB, Zhejiang Colon Cancer (LOVD), MMR Gene Unclassified Variants, and Mismatch Repair Genes Variant Databases. The c.687delA variant is predicted to cause a frameshift, which alters the amino acid sequence beginning at codon 230 and leads to a premature stop codon 16 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 27, 2020

Variant summary: MSH2 c.687delA (p.Ala230LeufsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251224 control chromosomes. c.687delA has been reported in the literature in multiple individuals affected with Hereditary Non-Polyposis Colon Cancer (eg. Jiang_2019, Mangold_2005, Wang_1999, Wolf_2005, Bai_1999). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation resulting in a stop codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 02, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91177). This variant is also known as a 1bp deletion at codons 227-229. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10404063, 10480359, 15849733, 15926618). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala230Leufs*16) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.687delA pathogenic mutation, located in coding exon 4 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 687, causing a translational frameshift with a predicted alternate stop codon (p.A230Lfs*16). This mutation has been reported in the germline of multiple individuals with HNPCC/Lynch syndrome from various ethnic backgrounds; several of which had tumors that demonstrated high microsatellite instability and/or loss of MSH2 and MSH6 staining on immunohistochemistry (IHC) and had family history meeting Amsterdam criteria (Wang Q et al. Hum. Genet.;105:79-85; Bai YQ et al. Int. J. Cancer, 1999 Aug;82:512-5; Wolf B et al. Wien Klin Wochenschr, 2005 Apr;117:269-77; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Stojcev Z et al. Acta Biochim Pol, 2013 Jun;60:195-8; Batte BA et al. Gynecol Oncol, 2014 Aug;134:319-25; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This mutation has also been reported in a patient with breast cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Of note, this alteration is also designated as "228-229 Del A" and "1 bp deletion codons 227-229" in published literature. 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

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: rs63749897; hg19: chr2-47639587;