7-6002611-C-T

Variant names:

• chr7-6002611-C-T
• rs114090343
• NM_000535.7:c.379G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000535.7(PMS2):​c.379G>A​(p.Ala127Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,611,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A127G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15 O:1
• Conservation: PhyloP100: 0.334
• Publications: 17 publications found

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]

PMS2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042134225).
• BP6: Variant 7-6002611-C-T is Benign according to our data. Variant chr7-6002611-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135069.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000236 (36/152286) while in subpopulation EAS AF = 0.00675 (35/5186). AF 95% confidence interval is 0.00499. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.379G>A	p.Ala127Thr	missense_variant	Exon 5 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.379G>A	p.Ala127Thr	missense_variant	Exon 5 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00673

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000474 AC: 119 AN: 251138 AF XY: 0.000449

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00593

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000288 AC: 421 AN: 1459476 Hom.: 0 Cov.: 31 AF XY: 0.000284 AC XY: 206 AN XY: 726058

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00947 AC: 376 AN: 39694

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111632

Other (OTH) AF: 0.000150 AC: 9 AN: 60196

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74456

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00675 AC: 35 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.000576 AC: 70

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:15 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4 Other:1

Jun 02, 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. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

May 25, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

May 15, 2017

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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.Ala127Thr variant was not identified in the literature nor was it identified in the following databases: the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant, Zhejiang Colon Cancer, Mismatch Repair Genes Variant, or Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs114090343); in ClinVar and Clinvitae databases as benign by GeneDx and Invitae; as likely benign by Ambry Genetics, Genetic Services laboratory, University of Chicago; and uncertain significance by Illumina Clinical Services. The variant was identified in control databases in 119 of 276900 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency variant in certain populations (Genome Aggregation Database Feb 27, 2017). Observation by population include: “other” in 1 of 6460 chromosomes (freq: 0.0002), European Non-Finnish in 3 of 126390 chromosomes (freq: 0.00002), East Asian in 109 of 18868 chromosomes (freq: 0.005777), and South Asian in 6 of 30782 chromosomes (freq: 0.000195). The variant was not observed in the African, Latino, Ashkenazi Jewish, European Finnish, populations. It was observed in homozygous form in an individual from our lab without features of biallelic mismatch repair syndrome increasing the likelihood this variant is benign. The p.Ala127Thr residue is not conserved in mammals and 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. The 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. -

Hereditary cancer-predisposing syndrome Benign:3

Apr 28, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2018

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. -

Dec 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Lynch syndrome Uncertain:1 Benign:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2 NM_000535.5:c.379G>A has a 70.8% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56 and 1.56 to 1, generated from evidence of seeing this as a somatic mutation in two independent tumors without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. -

Lynch syndrome 4 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 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. -

Jan 24, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Lynch syndrome 1 Uncertain:1

-

Ding PR Lab, Sun Yat-sen University Cancer Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PMS2-related disorder Benign:1

Apr 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.35
DANN	Benign	0.87
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.21	T;T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0042	T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L;.;.;L
PhyloP100		0.33
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.20	N;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.58	T;T;.;T
Sift4G	Benign	0.51	T;T;.;T
Polyphen		0.0	B;B;B;B
Vest4		0.17
MVP		0.68
MPC		0.036
ClinPred		0.0078	T
GERP RS		-8.2
Varity_R		0.038
gMVP		0.17
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs114090343; hg19: chr7-6042242; COSMIC: COSV56225134;