7-5987205-C-T

Variant names:

• chr7-5987205-C-T
• rs201167814
• NM_000535.7:c.1560G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000535.7(PMS2):​c.1560G>A​(p.Ala520Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,614,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A520A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (2 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17
• Conservation: PhyloP100: -0.210

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 7-5987205-C-T is Benign according to our data. Variant chr7-5987205-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138700.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=4, Uncertain_significance=1}. Variant chr7-5987205-C-T is described in Lovd as [Likely_benign]. Variant chr7-5987205-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000387 (59/152260) while in subpopulation AMR AF= 0.00137 (21/15280). AF 95% confidence interval is 0.00092. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1560G>A	p.Ala520Ala	synonymous_variant	Exon 11 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1560G>A	p.Ala520Ala	synonymous_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000342 AC: 86 AN: 251250 Hom.: 0 AF XY: 0.000331 AC XY: 45 AN XY: 135840

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000461 AC: 674 AN: 1461840 Hom.: 2 Cov.: 44 AF XY: 0.000465 AC XY: 338 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000559

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74436

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000461

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

May 12, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: BP4, BP7 -

Jun 26, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1560G>A (p.Ala520=) in PMS2 gene is a synonymous change that involves a non-conserved nucleotide. 4/5 programs in Alamut predict that this variant does not affect the normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population datasets of ExAC and gnomAD at a similar frequencies 0.00033 (38/120402 and 93/277018 chrs tested, respectively), which is about 3 times of the maximum expected allele frequency for a pathogenic PMS2 variant (0.00011). Sequence allignment and reads in ExAC support that the minor alleles reported in ExAC are not from the pseudogene. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited as Benign/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant was classified as benign. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

May 23, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 27, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 11, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 15, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Lynch syndrome 4 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Breast and/or ovarian cancer Benign:1

Jun 22, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Benign:1

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Ala520= variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs201167814) “With Uncertain significance allele”, ClinVar (classified benign by GeneDx, likely benign by Ambry Genetics, Invitae, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, and uncertain significance by Praxis fuer Humangenetik Tuebingen), Clinvitae (4x), and in control databases in 93 of 277018 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23986 chromosomes (freq: 0.00004), “Other” in 2 of 6464 chromosomes (freq: 0.0003), Latino in 16 of 34418 chromosomes (freq: 0.0005), European Non-Finnish in 66 of 126586 chromosomes (freq: 0.0005), East Asian in 4 of 18864 chromosomes (freq: 0.0002), European Finnish in 2 of 25782 chromosomes (freq: 0.00008), and South Asian in 2 of 30782 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish population. The p.Ala520= variant is not expected to have clinical significance because it does not result in a change of amino acid. This variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.3
DANN	Benign	0.48

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: rs201167814; hg19: chr7-6026836; COSMIC: COSV56224239;