7-5977677-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 12/21 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. 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

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 -9 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 id is 142421.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=9, Likely_benign=5, not_provided=1}. Variant chr7-5977677-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2356C>A	p.Leu786Met	missense_variant	14/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2356C>A	p.Leu786Met	missense_variant	14/15	1	NM_000535.7	P3

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

GnomAD3 exomes AF: 0.00114 AC: 285 AN: 250066 Hom.: 9 AF XY: 0.00169 AC XY: 228 AN XY: 135134

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 SAS exome AF: 0.00863

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

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000760

Gnomad4 SAS exome AF: 0.00992

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000975

Gnomad4 OTH exome AF: 0.000532

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

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.0000662

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000297

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000189 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

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 07, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 19, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Oct 10, 2023	- -

not provided Uncertain:1 Benign:4 Other:1

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2017	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. -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2019	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. -

Lynch syndrome 4 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 23, 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 04, 2023	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

Benign, criteria provided, single submitter

clinical testing

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

Apr 25, 2023

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;T;.;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.015	T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N;N;.;.;.;N
REVEL	Uncertain	0.38
Sift	Benign	0.11	T;T;.;.;.;T
Sift4G	Benign	0.24	T;T;.;.;.;T
Polyphen		0.71	P;P;.;.;P;B
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

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: rs576055272; hg19: chr7-6017308; COSMIC: COSV56224287;