16-23622972-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024675.4(PALB2):c.2993G>A(p.Gly998Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,614,050 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G998A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (41 hom., cov: 32)
  • Exomes 𝑓: 0.020 (348 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:26 O:1
• Conservation: PhyloP100: 3.23

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_024675.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0049796402).
• BP6: Variant 16-23622972-C-T is Benign according to our data. Variant chr16-23622972-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 126699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23622972-C-T is described in Lovd as [Likely_benign]. Variant chr16-23622972-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2602/152274) while in subpopulation NFE AF= 0.0227 (1547/68026). AF 95% confidence interval is 0.0218. There are 41 homozygotes in gnomad4. There are 1272 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 41 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2993G>A	p.Gly998Glu	missense_variant	9/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2993G>A	p.Gly998Glu	missense_variant	9/13	1	NM_024675.4	P1
	ENST00000561764.1	n.420-928C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2605 AN: 152156 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0164 AC: 4123 AN: 251452 Hom.: 47 AF XY: 0.0168 AC XY: 2288 AN XY: 135902

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0232

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00944

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0199 AC: 29158 AN: 1461776 Hom.: 348 Cov.: 32 AF XY: 0.0198 AC XY: 14384 AN XY: 727196

Gnomad4 AFR exome AF: 0.00358

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.0240

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0221

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0171 AC: 2602 AN: 152274 Hom.: 41 Cov.: 32 AF XY: 0.0171 AC XY: 1272 AN XY: 74448

Gnomad4 AFR AF: 0.00457

Gnomad4 AMR AF: 0.0219

Gnomad4 ASJ AF: 0.0302

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.0168

Gnomad4 NFE AF: 0.0227

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0220 Hom.: 84

Bravo AF: 0.0177

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00592 AC: 26

ESP6500EA AF: 0.0240 AC: 206

ExAC AF: 0.0158 AC: 1917

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.0306

EpiControl AF: 0.0278

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:26 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6 Other:1

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	- -

Familial cancer of breast Benign:6

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	Apr 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Oct 26, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 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. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
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. -

Ovarian cancer Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

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

Jan 01, 2022

- -

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

Aug 06, 2021

- -

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

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Gly998Glu variant was identified in 268 of 12272 proband chromosomes (freq 0.022) in multinational cohorts of BRCA1 and BRCA2 negative breast and breast-ovarian cancer families, male breast cancer cases, women with breast cancer who had a personal or family history of pancreatic cancer, families with 2 or more prostate cancer cases, unselected breast and ovarian cancers, and American hereditary prostate cancer families; and was identified in 129 of 7352 control chromosomes (freq. 0.018) (Balia 2010, Blanco 2012, Bogdanova 2011, Cao 2009, Catucci 2014, Ding 2011, Downs 2015 , Garcia 2009, Guenard 2010, Hofstatter 2011, Kuusisto 2011, Leyton 2015 , Pakkanen 2009, Prokofyeva 2012, Hellebrand 2011, Rahman 2007, Sauty de Chalon 2010, Silvestri 2010, Sluiter 2009, Teo 2013, Wong 2011, Tischkowitz 2008, Zheng 2012). Blanco et al (2012) identified the variant in 6 index cases, which also had 5 other PALB2 variants, with co-segregation analysis in one of the carriers suggesting that all 6 variants constituted a haplotype. In a study looking at BRCA1 positive and BRCA negative families, the PALB2 variant was found in 2 families who carried different BRCA1 mutations (332-11T-Gins59-ter75, and 300Cys-Gly (T-G)) (Downs 2015 ). In their study, Rahman et al (2007) found no overall evidence that PALB2 missense variants confer susceptibility to breast cancer, with 23% affected individuals and 24% controls carrying at least one nonsynonymous missense variant. The variant was also identified in dbSNP (ID: rs45551636) as “other” allele, Clinvitae database (classifications benign, likely benign, conflicting interpretations of pathogenicity), Fanconi Anemia Mutation Database (LOVD), the ClinVar database (classifications benign: Invitae, Ambry Genetics, Prevention Genetics, Counsyl, GeneDx, Pathway Genomics, PALB2 database , likely benign: Vantari Genetics, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Illumina Clinical Services Laboratory , and not provided: ITMI submitters). The variant was identified in control databases in 1917 of 121404 chromosomes at a frequency of 0.01579 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 237 of 10150 chromosomes (freq: 0.023), European (Non-Finnish) in 2781 of 126704 chromosomes (freq: 0.022), Other in 129 of 6466 chromosomes (freq: 0.02), European (Finnish) in 481 of 25784 chromosomes (freq: 0.019), Latino in 471 of 34418 chromosomes (freq: 0.014). The p.Gly998 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 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

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	0.26
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.1	D;D
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.28
MPC		0.38
ClinPred		0.012	T
GERP RS		5.8
Varity_R		0.80
gMVP		0.63

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: rs45551636; hg19: chr16-23634293; COSMIC: COSV55161905; COSMIC: COSV55161905;