7-5977677-G-T

Variant names:

• chr7-5977677-G-T
• rs576055272
• NM_000535.7:c.2356C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000535.7(PMS2):​c.2356C>A​(p.Leu786Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 150,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L786P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00069 (41 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:17 O:1
• Conservation: PhyloP100: 2.86
• Publications: 9 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014594287).
• BP6: Variant 7-5977677-G-T is Benign according to our data. Variant chr7-5977677-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142421.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.2356C>A	p.Leu786Met	missense	Exon 14 of 15	NP_000526.2
	PMS2	NM_001406866.1		c.2542C>A	p.Leu848Met	missense	Exon 15 of 16	NP_001393795.1
	PMS2	NM_001322014.2		c.2389C>A	p.Leu797Met	missense	Exon 14 of 15	NP_001308943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2356C>A	p.Leu786Met	missense	Exon 14 of 15	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.1153C>A	p.Leu385Met	missense	Exon 10 of 11	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.1716C>A		non_coding_transcript_exon	Exon 12 of 13	ENSP00000514464.1

Frequencies

GnomAD3 genomes AF: 0.000300 AC: 45 AN: 150230 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00114 AC: 285 AN: 250066 AF XY: 0.00169

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000655

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000692 AC: 1007 AN: 1455666 Hom.: 41 Cov.: 31 AF XY: 0.000976 AC XY: 707 AN XY: 724130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33282

American (AMR) AF: 0.0000895 AC: 4 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39460

South Asian (SAS) AF: 0.00992 AC: 851 AN: 85810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5742

European-Non Finnish (NFE) AF: 0.0000975 AC: 108 AN: 1107388

Other (OTH) AF: 0.000532 AC: 32 AN: 60140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000299 AC: 45 AN: 150332 Hom.: 0 Cov.: 30 AF XY: 0.000505 AC XY: 37 AN XY: 73322

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000488 AC: 2 AN: 40962

American (AMR) AF: 0.0000662 AC: 1 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00850 AC: 40 AN: 4704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10346

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

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67404

Other (OTH) AF: 0.00 AC: 0 AN: 2074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000896 Hom.: 0

ExAC AF: 0.00126 AC: 152

EpiCase AF: 0.000164

EpiControl AF: 0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:17 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:5

May 07, 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.

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 10, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 19, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

not provided Uncertain:1 Benign:4 Other:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: PP2, BS2

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-07-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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.Leu786Met variant was not identified in the literature nor was it identified in the COGR, MutDB, Insight Colon Cancer Gene Variant, Zhejiang Colon Cancer, Mismatch Repair Genes Variant, and the Insight Hereditary Tumors databases. Furthermore, the variant was not identified in the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs576055272) as with other allele, in the ClinVar and Clinvitae databases as benign by Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano; as likely benign by Ambry Genetics and Prevention Genetics; and as uncertain significance by GeneDx. In addition, the variant was identified in the Cosmic database 1X as pathogenic in a lobular carcinoma and in the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002). The variant was further identified in control databases in 287 of 244884 chromosomes (10 homozygous) at a frequency of 0.001 increasing the likelihood that this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 15242 chromosomes (freq: 0.00007), Other in 1 of 5466 chromosomes (freq: 0.0002), Latino in 3 of 33562 chromosomes (freq: 0.00009), European Non-Finnish in 15 of 110756 chromosomes (freq: 0.0001), East Asian in 1 of 17174 chromosomes (freq: 0.00006), and South Asian in 266 of 30658 chromosomes (freq: 0.009); it was not observed in the Ashkenazi Jewish and European Finnish, populations. The p.Leu786 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. This variant is classified as likely benign.

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 17, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted PMS2 c.2356C>A at the cDNA level, p.Leu786Met (L786M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). PMS2 Leu786Met was identified in at least one individual among a cohort of 145 patients who underwent PMS2 clinical testing, as well as in an individual with previously negative BRCA1/2 analysis (Vaughn 2010, Yadav 2016). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). PMS2 Leu786Met is located in the Endonuclease domain (Fukui 2011). In-silico analysis, including protein predictors and evolutionary conservation, supports that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Leu786Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:4

Jan 23, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.2356C>A (p.Leu786Met) results in a conservative amino acid change located in the MutL, C-terminal, dimerization domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 244884 control chromosomes, predominantly at a frequency of 0.0087 within the South Asian subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 77 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. However, this observance needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured, although the observance of a total of 10 homozygotes does support the actual PMS2 gene being captured. c.2356C>A has been reported in the literature in individuals with a personal or family history of cancer including colorectal cancer and breast cancer (Yadav 2017, Tung 2015, Roy 2009). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as benign (2x), likely benign (1x) and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 04, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lynch syndrome 4 Uncertain:1 Benign:2

Jul 23, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 rule this variant out of causing disease. Therefore, this variant is classified as benign.

Jul 07, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Apr 04, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.

Breast and/or ovarian cancer Benign:1

Apr 25, 2023

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

Significance: 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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.38
Sift	Benign	0.11	T
Sift4G	Benign	0.24	T
Polyphen		0.71	P
Vest4		0.40
MutPred		0.70		Gain of disorder (P = 0.0874)
MVP		0.78
MPC		2.9
ClinPred		0.027	T
GERP RS		2.7
Varity_R		0.13
gMVP		0.67
Mutation Taster		=92/8	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: rs576055272; hg19: chr7-6017308; COSMIC: COSV56224287;