rs45568339

chr16-23626394-G-Achr16-23626394-G-Cchr16-23626394-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_024675.4(PALB2):c.2590C>T(p.Pro864Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,614,176 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. P864H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (11 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:31 O:1
• Conservation: PhyloP100: 0.823

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00803414).
• BP6: Variant 16-23626394-G-A is Benign according to our data. Variant chr16-23626394-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 126669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626394-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2590C>T	p.Pro864Ser	missense_variant	7/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2590C>T	p.Pro864Ser	missense_variant	7/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00284 AC: 715 AN: 251474 Hom.: 2 AF XY: 0.00292 AC XY: 397 AN XY: 135914

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00348 AC: 5084 AN: 1461876 Hom.: 11 Cov.: 31 AF XY: 0.00352 AC XY: 2562 AN XY: 727240

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00387

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00279 AC: 425 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74454

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00376

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00427 Hom.: 2

Bravo AF: 0.00304

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00266 AC: 323

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:31 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:13

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2019	This variant is associated with the following publications: (PMID: 26564480, 28279176, 30521987, 25794774, 25666743, 20589654, 23448497, 23935836, 22052327, 22241545, 20852946, 21365267, 21618343, 21932393, 23824750, 18302019, 24728327, 24949998, 20722467, 26283626, 17200668, 26898890, 27153395, 29052111, 28717660, 29458332, 31757951, 31586400, 31636395) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 17, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PALB2: BP4, BS1:Supporting, BS3:Supporting -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 15, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 11, 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, criteria provided, single submitter	clinical testing	Vantari Genetics	Oct 07, 2015	- -

Familial cancer of breast Benign:4

Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	Invitae	Feb 01, 2024	- -

not specified Benign:3 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 23, 2016	- -
Likely 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	Genetic Services Laboratory, University of Chicago	Nov 29, 2019	- -

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.Pro864Ser variant was identified in 62 of 12244 proband chromosomes (frequency: 0.005) in multinational cohorts of BRCA1 and BRCA2 negative breast and breast-ovarian cancer families, male breast cancer cases, triple negative breast cancer cases, women with breast cancer who had a personal or family history of pancreatic cancer, familial pancreatic cancer, families with 2 or more prostate cancer cases, unselected breast and ovarian cancers, and hereditary prostate cancer families; and was identified in 14 of 3250 control chromosomes (freq. 0.004) (Balia 2010, Blanco 2012, Catucci 2014, Ding 2011, Downs 2015 , Garcia 2009, Guenard 2010, Hofstatter 2011, Hellebrand 2011, Rahman 2007, Sauty de Chalon 2010, Teo 2013, Zheng 2012, Zhen 2015, Adank 2011, Aoude 2014, Papi 2010). The variant was also identified in dbSNP (ID: rs45568339) as “Other”, ClinVar (classified as benign by Invitae, Ambry Genetics, Pathway Genomics; likely benign by GeneDx, Vantari Genetics, Illumina, PALB2 database, Cancer Genetics Laboratory, Peter MacCallum Cancer Center; classification not provided by ITMI), Clinvitae (with conflicting interpretations of pathogenicity), LOVD 3.0 (19X), and Zhejiang Colon Cancer Database (3X); and was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 755 (2 homozygous) of 277236 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following population at a frequency greater than 1%: Ashkenazi Jewish* in 113 of 10152 chromosomes (freq: 0.011). The p.Pro864Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 this variant meets our laboratory's criteria to be classified as benign. -

Breast carcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 19, 2021

Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative -

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

May 17, 2022

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 27, 2021

- -

Fanconi anemia complementation group N Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0087	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.90	N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D;D
Sift	Benign	0.12	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.58	.;P
Vest4		0.31
MVP		0.55
MPC		0.12
ClinPred		0.029	T
GERP RS		2.8
Varity_R		0.25
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45568339; hg19: chr16-23637715; COSMIC: COSV99848803; COSMIC: COSV99848803;