rs12532895

chr7-6003755-G-Achr7-6003755-G-Cchr7-6003755-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000535.7(PMS2):c.288C>T(p.Ala96=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.047 in 1,602,532 control chromosomes in the GnomAD database, including 5,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A96A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.047 (510 hom., cov: 32)
  • Exomes 𝑓: 0.047 (4605 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: 0.685

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 7-6003755-G-A is Benign according to our data. Variant chr7-6003755-G-A is described in ClinVar as [Benign]. Clinvar id is 91350.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-6003755-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.685 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.288C>T	p.Ala96=	synonymous_variant	4/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.288C>T	p.Ala96=	synonymous_variant	4/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 7192 AN: 152018 Hom.: 509 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0437

GnomAD3 exomes AF: 0.0804 AC: 19273 AN: 239762 Hom.: 1845 AF XY: 0.0819 AC XY: 10748 AN XY: 131214

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0866

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.351

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.0834

Gnomad NFE exome AF: 0.0294

Gnomad OTH exome AF: 0.0600

GnomAD4 exome AF: 0.0470 AC: 68116 AN: 1450394 Hom.: 4605 Cov.: 29 AF XY: 0.0498 AC XY: 35930 AN XY: 722026

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.0815

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.0840

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0566

GnomAD4 genome AF: 0.0473 AC: 7200 AN: 152138 Hom.: 510 Cov.: 32 AF XY: 0.0526 AC XY: 3913 AN XY: 74352

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.0536

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.343

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0869

Gnomad4 NFE AF: 0.0292

Gnomad4 OTH AF: 0.0499

Alfa AF: 0.0300 Hom.: 36

Bravo AF: 0.0427

Asia WGS AF: 0.243 AC: 844 AN: 3478

EpiCase AF: 0.0275

EpiControl AF: 0.0274

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Lynch syndrome 4 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 01, 2015	- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

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_noAF	Benign	-0.36
Cadd	Benign	9.8
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs12532895; hg19: chr7-6043386; COSMIC: COSV56219896; COSMIC: COSV56219896;