16-23630140-C-G

Position:

• chr16-23630140-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP1

This summary comes from the ClinGen Evidence Repository: The c.2014G>C variant in PALB2 is a missense variant predicted to cause a substitution of a glutamic acid by glutamine at amino acid 672 (p.Glu672Gln). This variant has a gnomAD v2.1.1 filtering allele frequency of 0.02846 in non-Finnish European population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in multiple protein assays (PMID:31636395, PMID:31757951, PMID:33964450); however, due to a lack of known positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BA1, BP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA151230/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.022 (63 hom., cov: 32)
  • Exomes 𝑓: 0.028 (652 hom.)
• Consequence: PALB2 ENST00000261584.9 missense
• Clinical Significance: Benign reviewed by expert panel B:30 O:1
• Conservation: PhyloP100: 0.103

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2014G>C	p.Glu672Gln	missense_variant	5/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2014G>C	p.Glu672Gln	missense_variant	5/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3367 AN: 152160 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0465

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0228 AC: 5725 AN: 251424 Hom.: 100 AF XY: 0.0241 AC XY: 3273 AN XY: 135898

Gnomad AFR exome AF: 0.00529

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0351

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0266

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0293

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0277 AC: 40430 AN: 1461866 Hom.: 652 Cov.: 33 AF XY: 0.0279 AC XY: 20287 AN XY: 727238

Gnomad4 AFR exome AF: 0.00508

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0357

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0259

Gnomad4 FIN exome AF: 0.0195

Gnomad4 NFE exome AF: 0.0300

Gnomad4 OTH exome AF: 0.0273

GnomAD4 genome AF: 0.0221 AC: 3362 AN: 152278 Hom.: 63 Cov.: 32 AF XY: 0.0220 AC XY: 1638 AN XY: 74474

Gnomad4 AFR AF: 0.00592

Gnomad4 AMR AF: 0.0253

Gnomad4 ASJ AF: 0.0465

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0236

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0298

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.0282 Hom.: 50

Bravo AF: 0.0224

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.00706 AC: 31

ESP6500EA AF: 0.0315 AC: 271

ExAC AF: 0.0224 AC: 2718

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.0389

EpiControl AF: 0.0362

ClinVar

Significance: Benign

Submissions summary: Benign:30 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 302/12994=2.3% -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2013	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Familial cancer of breast Benign:6

Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 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. -
Likely benign, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.2014G>C variant in PALB2 is a missense variant predicted to cause a substitution of a glutamic acid by glutamine at amino acid 672 (p.Glu672Gln). This variant has a gnomAD v2.1.1 filtering allele frequency of 0.02846 in non-Finnish European population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in multiple protein assays (PMID: 31636395, PMID: 31757951, PMID: 33964450); however, due to a lack of known positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BA1, BP1) -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 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. -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Oct 26, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 18, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 23, 2018	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 07, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Maximiliano Zeballos, Melissa DeRycke. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Malignant tumor of breast Benign:2

Benign, no assertion criteria provided	clinical testing	Center of Medical Genetics and Primary Health Care	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PALB2 p.Glu672Gln variant was identified in 210 of 6690 proband chromosomes (frequency: 0.03) from individuals or families with breast and/or ovarian cancer (Bogdanova 2011, Rahman 2007, Teo 2013, Adank 2011, Nguyen-Dumont 2013, Kluska 2017). The variant was also identified in ClinVar (10x benign: Invitae, Ambry Genetics, Vantari Genetics, Color Genomics, Prevention Genetics, Counsyl, GeneDx, Pathway Genomics, PALB2 database; 2x likely benign: MacCallum Cancer Genetics, Illumina; 1x not provided: ITMI), MutDB (Mut Prediction score of 0.135 with link to UniProtKB/Swiss-Prot Q86YC2: Variant p.Glu672Gln which classifies this variant as a polymorphism-not reported to be implicated in disease), LOVD 3.0 (21x “does not affect function”; 3x not classified), Zhejiang University Database (5x "pathogenicity unknown"), databases. The variant was not identified in the COSMIC database. The variant was identified in control databases in 6201 of 277202 chromosomes at a frequency of 0.02 including 104 homozygous individuals increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: Ashkenazi Jewish* in 355 of 10152 chromosomes (freq: 0.035), European (Non-Finnish) in 3698 of 126702 chromosomes (freq: 0.029), Other in 174 of 6466 chromosomes (freq: 0.027), South Asian in 809 of 30782 chromosomes (freq: 0.026), European (Finnish) in 510 of 25782 chromosomes (freq: 0.02), Latino in 531 of 34420 chromosomes (freq: 0.015). The p.Glu672Gln residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 this variant meets our laboratory's criteria to be classified as benign. -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 26, 2022

- -

Fanconi anemia complementation group N Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Breast-ovarian cancer, familial, susceptibility to, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.81	N;N
REVEL	Benign	0.029
Sift	Benign	0.096	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.23	.;B
Vest4		0.046
MPC		0.085
ClinPred		0.0011	T
GERP RS		1.8
Varity_R		0.036
gMVP		0.18

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: rs45532440; hg19: chr16-23641461; COSMIC: COSV55161919;