2-47482929-C-T

Position:

• chr2-47482929-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BP6_Strong

The NM_000251.3(MSH2):​c.2785C>T​(p.Arg929Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,611,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:6 B:6
• Conservation: PhyloP100: 2.34

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 Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00713 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• BP6: Variant 2-47482929-C-T is Benign according to our data. Variant chr2-47482929-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 91045.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5, Benign=2}. Variant chr2-47482929-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2785C>T	p.Arg929Ter	stop_gained	16/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2785C>T	p.Arg929Ter	stop_gained	16/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151974 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000845 AC: 21 AN: 248568 Hom.: 0 AF XY: 0.0000594 AC XY: 8 AN XY: 134568

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000927

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1459282 Hom.: 0 Cov.: 31 AF XY: 0.0000262 AC XY: 19 AN XY: 725822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000430

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152092 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74364

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000742 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:6 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 14, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 28, 2021	- -

Lynch syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2023	Nonsense variant predicted to result in protein truncation as the last 6 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Occurred in cis with a nonsense variant in the MSH6 gene in eight unrelated Portuguese Lynch syndrome families; tumor immunohistochemistry (IHC) revealed normal MSH2 expression in 5/8 cases and absence of MSH6 protein in 7/7 cases with interpretable data (PMID: 26446363); Observed in two individuals with colorectal cancer, co-occurring with a pathogenic MSH2 founder pathogenic variant in one individual, as well as in individuals with breast and/or ovarian cancer (PMID: 12624141, 21681552, 24240112, 26824983, 28050010, 28724667, 32068069, 35264596, 35449176, 35534704); This variant is associated with the following publications: (PMID: 12624141, 28127413, 28724667, 21681552, 24344984, 24240112, 26824983, 28874130, 28332257, 29752822, 29506494, 28050010, 9774676, 18822302, 21120944, 27873144, 33015532, 31569399, 26689913, 32029870, 31207149, 35264596, 35980532, 32068069, 35534704, 28514183, 26446363, 35449176) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 06, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	Variant summary: MSH2 c.2785C>T (p.Arg929X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. This variant leads to encoding a protein that is 6 AA shorter and without interruption of any known functional domain (Pinto_MSH2_JHG_2016). Truncations downstream of this position have not been classified as pathogenic by our laboratory or in ClinVar. The variant allele was found at a frequency of 8.4e-05 in 248768 control chromosomes, predominantly at a frequency of 0.00093 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2785C>T has been reported in the literature in individuals affected with colorectal cancer, lynch syndrome, breast cancer, and prostate cancer (examples: Parc_2003, Valentin_2011, Feliubadalo_2017, Lin_2016, Pennington_2013, Pinto_2016, Lu_2015, Sun_2017, Li_2019, Kwong_2020, Fang_2023). However, many of these cases had one or more co-occurrences with other pathogenic variants (MSH2 c. 942+3A>T; MSH6 c.1030C>T, p.Gln344Ter; BRCA1 c.190T>C, p.C64R; BRCA2 c.9090dupA, p.T3030fs; BRCA1 c.4327C>T, p.R1443X) (Valentin_2011, Pinto_2016, Sun2017 and Li_2019 ), providing supporting evidence for a benign role. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 16451135, 28127413, 24344984, 36522531, 28050010, 32068069, 29752822, 26824983, 26689913, 12624141, 24240112, 26446363, 28724667, 21681552). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments - pathogenic (n=1), likely benign/benign (n=4) and VUS (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Arg989X variant was identified in 10 of 474 proband chromosomes (frequency: 0.021) from South American and Portugese individuals or families with Lynch syndrome, meeting Amsterdam or Bethesda criteria, and was not identified in 200 control chromosomes from healthy individuals (Valentin 2011, Pinto 2015). However eight of the nine patients identified by Pinto et al. were also found to have a co-occurring pathogenic MSH6 mutation (c.1030C>T, p.Gln344X), five of the eight double mutant tumors had normal MSH2 expression and the ninth patient lacked a family history of colon cancer. The patient identified by Valentin et al. was also found to have a co-occurring pathogenic mutation, MSH2: c.942+3A>T (Valentin 2011). The variant was also identified in dbSNP (ID: rs551060742) “With pathogenic allele”, 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 9 of 113840 chromosomes (frequency: 0.00008) (or 9 individuals from a population of 8454 East Asian individuals, frequency 0.001); Clinvitae database (classification pathogenic), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic, and reviewed by an expert panel; being classified as pathogenic by InSight, and uncertain significance by Invitae), and UMD (9x with a “causal” classification). The above classifications were only updated as recently as 2014. The variant was also identified by our laboratory in 1 individual of Portugese background, with colon cancer, co-occurring with a pathogenic MSH6 mutation (c.1030C>T, p.Gln344X), as seen in the Portugese families from Pinto’s study (Pinto_2015_26446363). The p.Arg989X variant leads to a premature stop codon at position 989, which is predicted to lead to 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. However, the p.Arg989X encodes a protein 6 amino acids short of the wildtype transcript, without interruption of any known functional domain. Notably, this mutation occurs in the last exon of the MSH2 gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. However, due to conflicting interpretations above, this variant is classified as a variant of unknown significance. -

Lynch syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Nonsense variant after codon 888 in MSH2 = VUS -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.75
GERP RS		2.6

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: rs551060742; hg19: chr2-47710068; COSMIC: COSV51878909;