7-6005969-C-G

Position:

• chr7-6005969-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BP6 BS1

The NM_000535.7(PMS2):​c.86G>C​(p.Gly29Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,610,736 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:12 O:1
• Conservation: PhyloP100: 7.54

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 Likely_benign. Variant got -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.11153719).
• BP6: Variant 7-6005969-C-G is Benign according to our data. Variant chr7-6005969-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41721.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=9, not_provided=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000618 (94/152214) while in subpopulation SAS AF= 0.00104 (5/4818). AF 95% confidence interval is 0.000495. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.86G>C	p.Gly29Ala	missense_variant	2/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.86G>C	p.Gly29Ala	missense_variant	2/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000614 AC: 151 AN: 245776 Hom.: 1 AF XY: 0.000544 AC XY: 73 AN XY: 134160

Gnomad AFR exome AF: 0.0000665

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00674

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000518

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.000490 AC: 714 AN: 1458522 Hom.: 1 Cov.: 31 AF XY: 0.000480 AC XY: 348 AN XY: 725592

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00693

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000279

Gnomad4 FIN exome AF: 0.000401

Gnomad4 NFE exome AF: 0.000387

Gnomad4 OTH exome AF: 0.000864

GnomAD4 genome AF: 0.000618 AC: 94 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74398

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000440 Hom.: 0

Bravo AF: 0.000461

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000433 AC: 2

ExAC AF: 0.000488 AC: 57

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PMS2: PP3, BP2, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PMS2 p.Gly29Ala variant was identified 2 exome sequencing studies looking at cancer susceptibility genes in subjects of preterm birth or atherosclerotic phenotype, being observed in 5 of 2506 proband chromosomes (frequency 0.002) (Johnston 2012, Bodian 2014). The variant was also identified in dbSNP (ID: rs146176004) “With other allele”, ClinVar (with conflicting interpretations of pathogenicity, submitters: likely benign by GeneDx, Invitae, Ambry Genetics; uncertain significance by Illumina and Biesecker Lab/Human Development Section-NIH; and classification not provided by ITMI), Clinvitae (4x), and Insight Hereditary Tumors Database (3x); but was not identified in the Genesight-COGR, Cosmic, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database. The variant was identified in control databases in 160 (1 homozygous) of 271376 chromosomes at a frequency of 0.0006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations: African in 1 of 22874 chromosomes (frequency: 0.00004), Other in 9 of 6380 chromosomes (frequency: 0.001), Latino in 3 of 34310 chromosomes (frequency: 0.00009),European Non-Finnish in 63 (1 homozyogus) of 122742 chromosomes (frequency: 0.0005),European Finnish in 13 of 25778 chromosomes (frequency: 0.0005),Ashkenazi Jewish in 62 of 9996 chromosomes (frequency: 0.006), and South Asian in 9 of 30552 chromosomes (frequency: 0.0003). The p.Gly29 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 17, 2023	The PMS2 c.86G>C;p.Gly29Ala variant has been published in the literature in reportedly healthy individuals (Bodian 2014, Johnston 2012) as well as individuals with colorectal cancer or breast cancer (Goodenberger 2016, Nikitin 2020, Tung 2016, Yurgelun 2017). Several of these individuals had other known pathogenic or risk factor variants in cancer susceptibility genes. This variant is also reported in ClinVar (Variation ID: 41721). This variant is found in the general population with an allele frequency of 0.057% (150/264,494 alleles, including 1 homozygote) in the non-cancer cohort of Genome Aggregation Database with a higher frequency observed in the Ashkenazi Jewish population (0.63%; 62/9,774 alleles). Although this frequency is higher than expected for a pathogenic variant, this variant was significantly associated with breast cancer in a recent case-control study (Nikitin 2020). The glycine at codon 29 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.825). Due to conflicting information, the clinical significance of the p.Gly29Ala variant is uncertain at this time. -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

not specified Benign:4 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2017	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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2022	Variant summary: PMS2 c.86G>C (p.Gly29Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 245776 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is benign. c.86G>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with a pathogenic variant has been reported (PMS2 exon 10 deletion, Goodenberger_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=9, VUS n=5). Based on the evidence outlined above, the variant was classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 28, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 22, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2015	- -

Lynch syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	- -

Lynch syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, 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

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 22, 2023

- -

PMS2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;T
Polyphen		1.0	D;D
Vest4		0.96
MVP		0.93
MPC		0.28
ClinPred		0.12	T
GERP RS		5.7
Varity_R		0.88
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146176004; hg19: chr7-6045600;