7-5987234-T-C

Position:

• chr7-5987234-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000535.7(PMS2):​c.1531A>G​(p.Thr511Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,614,066 control chromosomes in the GnomAD database, including 678 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T511M) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.021 (53 hom., cov: 32)
  • Exomes 𝑓: 0.027 (625 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel B:26 O:1
• Conservation: PhyloP100: -0.352

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029952526).
• BP6: Variant 7-5987234-T-C is Benign according to our data. Variant chr7-5987234-T-C is described in ClinVar as [Benign]. Clinvar id is 41703.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5987234-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0215 (3267/152240) while in subpopulation NFE AF= 0.0277 (1886/68026). AF 95% confidence interval is 0.0267. There are 53 homozygotes in gnomad4. There are 1694 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 53 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1531A>G	p.Thr511Ala	missense_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.1531A>G	p.Thr511Ala	missense_variant	11/15	1	NM_000535.7	ENSP00000265849	P3

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3267 AN: 152122 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0246 AC: 6176 AN: 251328 Hom.: 105 AF XY: 0.0254 AC XY: 3446 AN XY: 135878

Gnomad AFR exome AF: 0.00481

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0315

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0200

Gnomad FIN exome AF: 0.0544

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0272 AC: 39709 AN: 1461826 Hom.: 625 Cov.: 47 AF XY: 0.0270 AC XY: 19627 AN XY: 727210

Gnomad4 AFR exome AF: 0.00490

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0315

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0208

Gnomad4 FIN exome AF: 0.0516

Gnomad4 NFE exome AF: 0.0288

Gnomad4 OTH exome AF: 0.0248

GnomAD4 genome AF: 0.0215 AC: 3267 AN: 152240 Hom.: 53 Cov.: 32 AF XY: 0.0228 AC XY: 1694 AN XY: 74434

Gnomad4 AFR AF: 0.00631

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.0381

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.0538

Gnomad4 NFE AF: 0.0277

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0258 Hom.: 20

Bravo AF: 0.0181

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0283 AC: 109

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0281 AC: 242

ExAC AF: 0.0250 AC: 3041

EpiCase AF: 0.0285

EpiControl AF: 0.0268

ClinVar

Significance: Benign

Submissions summary: Benign:26 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Lynch syndrome 4 Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 11, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 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	Jan 02, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 05, 2018	- -

Lynch syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

not provided Benign:2

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Endometrial carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

PMS2, EXON11, c.1531A>G, p.Thr511Ala, Benign (ACMG 5) The c.1531A>G variant was identified in 6 of 368 proband chromosomes (frequency: 0.016) from individuals or families with HNPCC and Lynch syndrome; however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was present in individuals that tested immunohistocompatibility PMS2 negative but positive for MLH1, MSH2 and MSH 6. Tumours were also found to be microsatellite instability high. (10479499_Basil_1999, 15256438_Nakagawa, 16619239_Clenndening_2006, 24027009_Drost_2013) The variant was also identified in dbSNP (ID: rs2228007) “With untested allele”, with a minor allele frequency of 0.011 (1000 Genomes Project), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, and ClinVar database as a benign variant.The variant was classified as a benign/likely benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) with 6 separate submitters. The variant was classified as “unclassified” by a clinical laboratory within the Canadian Open Genetics Repository (http://opengenetics.ca/). This variant was identified in the 1000 Genomes Project in 26 of 2178 chromosomes (frequency: 0.0119), Exome Variant Server project in 270 of 13006 European American/African American alleles (frequency: 0.02), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Thr511 residue is not conserved in mammals and the variant amino acid Threonine (Thr) is present in Macaques and Trichoplax adhaerens, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity but it increases the likelihood that this variant does not have clinical significance. The c.1531A>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) In summary, based on the above information, the clinical significance of this variant satisfies our laboratory requirements as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.32
DANN	Benign	0.17
DEOGEN2	Benign	0.087	T;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.40	T;T;.;T;.
MetaRNN	Benign	0.0030	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.76	N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.75	N;N;.;.;.
REVEL	Benign	0.031
Sift	Benign	0.76	T;T;.;.;.
Sift4G	Benign	0.88	T;T;.;.;.
Polyphen		0.0	B;B;.;.;B
Vest4		0.017
MPC		0.036
ClinPred		0.0021	T
GERP RS		1.9
Varity_R		0.016
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2228007; hg19: chr7-6026865; COSMIC: COSV104554297;