7-5977709-T-C

Position:

• chr7-5977709-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_000535.7(PMS2):​c.2324A>G​(p.Asn775Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00027 (24 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:26 O:1
• Conservation: PhyloP100: 4.85

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15660042).
• BP6: Variant 7-5977709-T-C is Benign according to our data. Variant chr7-5977709-T-C is described in ClinVar as [Benign]. Clinvar id is 36689.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5977709-T-C is described in Lovd as [Likely_benign]. Variant chr7-5977709-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2324A>G	p.Asn775Ser	missense_variant	14/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2324A>G	p.Asn775Ser	missense_variant	14/15	1	NM_000535.7	ENSP00000265849	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 169 AN: 150216 Hom.: 2 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.000613

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000783

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000289

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00195

GnomAD3 exomes AF: 0.000252 AC: 63 AN: 249826 Hom.: 3 AF XY: 0.000230 AC XY: 31 AN XY: 135022

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000382

Gnomad OTH exome AF: 0.000656

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000268 AC: 390 AN: 1452696 Hom.: 24 Cov.: 32 AF XY: 0.000263 AC XY: 190 AN XY: 722712

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00112 AC: 169 AN: 150318 Hom.: 2 Cov.: 30 AF XY: 0.00117 AC XY: 86 AN XY: 73352

Gnomad4 AFR AF: 0.000611

Gnomad4 AMR AF: 0.00112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000785

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000289

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.00193

Alfa AF: 0.000625 Hom.: 2

ExAC AF: 0.000545 AC: 66

EpiCase AF: 0.00132

EpiControl AF: 0.000715

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:26 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 4 Benign:6

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 18, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 11, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 22, 2016	- -

not specified Benign:5 Other:1

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2018	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	This variant is associated with the following publications: (PMID: 22949387, 24728327, 22594646, 28347324) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	PMS2: PP2, BS2 -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 23, 2014	This alteration is classified as 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, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 16, 2014	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 27, 2021	- -

Lynch syndrome Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2013	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Uncertain significance, flagged submission	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -

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

Sep 13, 2022

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Lynch syndrome 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Endometrial carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

PMS2, Exon14, c.2324A>G, p. Asn775Ser, Benign, ACMG 5 The c.2324A>G variant was identified in 32 of 1428 proband chromosomes (frequency: 0.022) from individuals or families with HNPCC or Lynch syndrome (20698049_sheng_2010, 14756672_Thompson_2004, Clendenning_2006_16619239); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs17420802 ) “With benign allele”, HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, and the ClinVar database by 7 submitters as benign. The p.Asn775 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asn775Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The c.2324A>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.022
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;.;D;.;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D;D;.;.;.;D
REVEL	Uncertain	0.33
Sift	Benign	0.22	T;T;.;.;.;T
Sift4G	Benign	0.17	T;T;.;.;.;T
Polyphen		0.76	P;D;.;.;D;B
Vest4		0.39
MVP		0.82
MPC		2.1
ClinPred		0.20	T
GERP RS		4.6
Varity_R		0.35
gMVP		0.37

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: rs17420802; hg19: chr7-6017340; COSMIC: COSV56224196;