7-5995580-T-C

Variant names:

• chr7-5995580-T-C
• rs116788608
• NM_000535.7:c.857A>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000535.7(PMS2):​c.857A>G​(p.Asp286Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:4 O:2
• Conservation: PhyloP100: 7.65

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 -1 ACMG points.

• BP6: Variant 7-5995580-T-C is Benign according to our data. Variant chr7-5995580-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127798.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=9, not_provided=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.857A>G	p.Asp286Gly	missense_variant	Exon 8 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.857A>G	p.Asp286Gly	missense_variant	Exon 8 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251434 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 174 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74466

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000190 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:4 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.857A>G (p.Asp286Gly) variant has been reported in the published literature in individuals with colorectal cancer (PMIDs: 35430768 (2022), 34680242 (2021), 31992580 (2020)), Lynch syndrome-associated cancer or polyps (PMID: 25980754 (2015)), breast cancer (PMIDs: 34326862 (2021), 28503720 (2017)), ovarian cancer (PMID: 26689913 (2015)), pancreatic cancer (PMID: 28726808 (2018)), leukemia (PMID: 30760869 (2019)), and liposarcoma (PMID: 37536918 (2023)). It has also been observed in reported healthy individuals (PMIDs: 24728327 (2014), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). In an individual with endometrial cancer, this variant co-occurred with a pathogenic variant in the MSH6 gene, suggesting it was not the primary cause of disease (PMID: 26517685 (2015)). The frequency of this variant in the general population, 0.0002 (26/129148 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Aug 27, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 26517685, 24728327, 26689913, 28503720, 11574484, 28726808, 31992580, 34680242, 30760869, 34326862, 31391288, 35430768, 37536918, 33471991) -

-

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 4 Uncertain:2 Benign:1

Aug 02, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Lynch syndrome Uncertain:2

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glycine at codon 286 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast, pancreatic, ovarian and colorectal cancer and/or polyps (PMID: 28503720, 26689913, 26517685, 25980754, 28726808, 31391288, 34680242, 33471991) and in healthy individuals (PMID: 24728327, 33471991). Two of these individuals, one affected with ovarian cancer and the other suspected of Lynch syndrome, also had a pathogenic MSH6 co-variant (PMID: 26689913, 26517685). This variant has been identified in 36/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Feb 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glycine at codon 286 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast, pancreatic, ovarian and colorectal cancer and/or polyps (PMID: 28503720, 26689913, 26517685, 25980754, 28726808, 31391288, 34680242, 33471991) and in healthy individuals (PMID: 24728327, 33471991). Two of these individuals, one affected with ovarian cancer and the other suspected of Lynch syndrome, also had a pathogenic MSH6 co-variant (PMID: 26689913, 26517685). This variant has been identified in 36/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 22, 2021

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. -

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Nov 09, 2023

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.857A>G (p.Asp286Gly) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) within the S5 domain 2-like fold (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 1614058 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.857A>G has been reported in the literature in several individuals affected with Lynch Syndrome-related cancers (e.g., Yurgelun_2015, Li_2020, Wang_2020, Jori_2016, Rummel_2017, Svensson_2022, Frostberg_2021, Chaffee_2018), however without strong evidence for causality (e.g., lack of co-segregation data) in all cases. In one of these cases a co-occurrence with a pathogenic variant was reported (MSH6 c.2569_2572del, p.Asp857Phefs10*; Jori_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 28726808, 26517685, 31391288, 26689913, 30760869, 28503720, 35430768, 25980754, 31992580, 34680242, 34326862, 37536918). Ten submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n = 7; likely benign, n = 3). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer Uncertain:1

Jan 04, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PMS2-related disorder Uncertain:1

Mar 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 c.857A>G variant is predicted to result in the amino acid substitution p.Asp286Gly. This variant has been reported in two individuals with suspected Lynch syndrome, however, one these individuals also carried a pathogenic MSH6 variant (Yurgelun et al. 2015. PubMed ID: 25980754; Jori et al. 2015. PubMed ID: 26517685). Additionally, this variant was also present in an individual with ovarian cancer (Lu et al. 2015. PubMed ID: 26689913), an unrelated patient with breast cancer (Rummel. 2017. PubMed ID: 28503720), and an unrelated patient with pancreatic cancer (Supp. Table 2, Chaffee et al. 2018. PubMed ID: 28726808). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127798/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome 1 Uncertain:1

Jul 24, 2014

Pathway Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome;C5436817:Mismatch repair cancer syndrome 4 Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;.;D;.
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.7	D;D;.;.;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.029	D;D;.;.;.
Sift4G	Uncertain	0.032	D;D;.;.;.
Polyphen		0.12	B;B;.;.;B
Vest4		0.73
MVP		0.93
MPC		0.063
ClinPred		0.51	D
GERP RS		5.8
Varity_R		0.77
gMVP		0.67

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: rs116788608; hg19: chr7-6035211;