rs1805320

Positions:

• chr7-5987277-G-A
• chr7-5987277-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000535.7(PMS2):​c.1488C>T​(p.His496His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,613,848 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.021 (121 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (86 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Benign reviewed by expert panel B:22
• Conservation: PhyloP100: -1.68

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-5987277-G-A is Benign according to our data. Variant chr7-5987277-G-A is described in ClinVar as [Benign]. Clinvar id is 91304.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5987277-G-A is described in Lovd as [Benign]. Variant chr7-5987277-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1488C>T	p.His496His	synonymous_variant	11/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1488C>T	p.His496His	synonymous_variant	11/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3267 AN: 152072 Hom.: 121 Cov.: 31

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00873

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00603 AC: 1515 AN: 251386 Hom.: 44 AF XY: 0.00423 AC XY: 575 AN XY: 135880

Gnomad AFR exome AF: 0.0798

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00232 AC: 3389 AN: 1461658 Hom.: 86 Cov.: 43 AF XY: 0.00197 AC XY: 1433 AN XY: 727138

Gnomad4 AFR exome AF: 0.0762

Gnomad4 AMR exome AF: 0.00499

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.0215 AC: 3267 AN: 152190 Hom.: 121 Cov.: 31 AF XY: 0.0204 AC XY: 1515 AN XY: 74420

Gnomad4 AFR AF: 0.0738

Gnomad4 AMR AF: 0.00872

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.00615 Hom.: 8

Bravo AF: 0.0249

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Lynch syndrome 4 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 02, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 22, 2016	- -

Hereditary cancer-predisposing syndrome Benign:3

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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 22, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 26, 2021

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS2 p.His496= variant was identified in the literature, although the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs1805320) as “with benign allele” and ClinVar (classified as benign by Ambry Genetics, Color, Invitae, Counsyl and 6 other submitters; and as likely benign by True Health Diagnostics and Illumina). The variant was identified in control databases in 2168 of 282,774 chromosomes (70 homozygous) at a frequency of 0.008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1934 of 24,924 chromosomes (freq: 0.08), Latino in 163 of 35,440 chromosomes (freq: 0.005), Other in 22 of 7220 chromosomes (freq: 0.003), South Asian in 10 of 30,616 chromosomes (freq: 0.0003), European in 36 of 129,170 chromosomes (freq: 0.0003), Ashkenazi Jewish in 1 of 10,368 chromosomes (freq: 0.0001), East Asian in 1 of 19,946 chromosomes (freq: 0.00005), and Finnish in 1 of 25,090 chromosomes (freq: 0.00004). The variant was observed with a co-occurring, pathogenic PMS2 variant (p.SerGlyfs*3) in an individual with colorectal cancer (Nomura 2015), decreasing the likelihood that this variant has clinical significance. The p.His496= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.11
DANN	Benign	0.58

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: rs1805320; hg19: chr7-6026908; COSMIC: COSV104554368;