16-23634974-T-C

Position:

• chr16-23634974-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_024675.4(PALB2):​c.1572A>G​(p.Ser524Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00466 in 1,614,194 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (17 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: -0.526

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]

PALB2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-23634974-T-C is Benign according to our data. Variant chr16-23634974-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 126608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23634974-T-C is described in Lovd as [Likely_benign]. Variant chr16-23634974-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.526 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1572A>G	p.Ser524Ser	synonymous_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1572A>G	p.Ser524Ser	synonymous_variant	4/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 468 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00516

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00320 AC: 805 AN: 251492 Hom.: 2 AF XY: 0.00335 AC XY: 455 AN XY: 135922

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00481

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00483 AC: 7061 AN: 1461892 Hom.: 17 Cov.: 33 AF XY: 0.00487 AC XY: 3541 AN XY: 727246

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00334

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.00565

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.00307 AC: 468 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00307 AC XY: 229 AN XY: 74480

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00516

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00401 Hom.: 0

Bravo AF: 0.00298

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:27

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:11

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PALB2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2021	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary cancer-predisposing syndrome Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 26, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 22, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 02, 2020	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -

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 and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 12, 2023

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Ser524= variant was identified in 53 of 11538 proband chromosomes (frequency: 0.005) from Dutch, Spanish, German, Russian, American, British, Australian and Polish individuals or families with BRCA1/2 negative ovarian, pancreatic and female and male breast cancer with or without a family history of breast cancer and was identified in 48 of 7064 control chromosomes from healthy individuals (Adank 2011, Blanco 2012, Bogdanova 2011, Ding 2011, Garcia 2009, Hellebrand 2011, Hofstatter 2011, Kluska 2017, Rahman 2007, Teo 2013, Thompson 2015, Tischkowitz 2008). The variant was also identified in dbSNP (ID: rs45472400) “With other allele”, ClinVar (classified benign by Invitae, GeneDx, Quest Diagnostics, ARUP Laboratories, PALB2 database; and likely benign by Ambry Genetics, Illumina, Praxis fuer Humangenetik Tuebingen, Peter MacCallum cancer Centre and Institute for biomarker Research, Clinvitae (6x), Zhejiang Colon Cancer Database (2x), and was not identified in Cosmic. The variant was identified in control databases in 899 (2 homozygous) of 277242 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of the observations by population include African in 22 of 24026 chromosomes (freq. 0.0009), other in 14 of 6468 chromosomes (freq. 0.002), Latino in 86 (1 homozygous) of 34420 chromosomes (freq. 0.002), European Non-Finnish in 621 (1 homozygous) of 126732 chromosomes (freq. 0.005), Ashkenazi Jewish in 2 of 10152 chromosomes (freq:0.0002), European Finnish in 44 of 25792 chromosomes (freq:0.002) and South Asian in 110 of 30782 chromosomes (freq. 0.004); it was not seen in the East Asian population. The p.Ser524= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. 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
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs45472400; hg19: chr16-23646295; COSMIC: COSV104552865; COSMIC: COSV104552865;