chr16-23607914-A-C

Position:

• chr16-23607914-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024675.4(PALB2):​c.3300T>G​(p.Thr1100Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,614,080 control chromosomes in the GnomAD database, including 732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (72 hom., cov: 31)
  • Exomes 𝑓: 0.028 (660 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 0.305

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-23607914-A-C is Benign according to our data. Variant chr16-23607914-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 126730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23607914-A-C is described in Lovd as [Benign]. Variant chr16-23607914-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.305 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3300T>G	p.Thr1100Thr	synonymous_variant	12/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3300T>G	p.Thr1100Thr	synonymous_variant	12/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3870 AN: 152138 Hom.: 72 Cov.: 31

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0237 AC: 5950 AN: 251488 Hom.: 104 AF XY: 0.0248 AC XY: 3367 AN XY: 135920

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0163

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: 0.0293

GnomAD4 exome AF: 0.0279 AC: 40855 AN: 1461824 Hom.: 660 Cov.: 32 AF XY: 0.0282 AC XY: 20473 AN XY: 727224

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0357

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0258

Gnomad4 FIN exome AF: 0.0195

Gnomad4 NFE exome AF: 0.0299

Gnomad4 OTH exome AF: 0.0281

GnomAD4 genome AF: 0.0254 AC: 3865 AN: 152256 Hom.: 72 Cov.: 31 AF XY: 0.0253 AC XY: 1885 AN XY: 74444

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.0464

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0239

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.0299

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0283 Hom.: 37

Bravo AF: 0.0260

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0389

EpiControl AF: 0.0363

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 08, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 24, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 23, 2018	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Familial cancer of breast Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

Jan 13, 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

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Thr1100= variant was identified in 196 of 6158 proband chromosomes (frequency: 0.03) from individuals or families with breast cancer, ovarian cancer, or malignant melanoma (Aoude 2014, Erkko 2007, Rahman 2007, Kluska 2017, Catucci 2014). The variant was also identified in ClinVar (classified as benign by Invitae, Ambry Genetics, Prevention Genetics, and three other submitters; and as likely benign by three submitters), LOVD 3.0 (20x as not affecting function), and then Zhejiang Colon Cancer Database (5 entries classified as “probably no pathogenicity”). The variant was not identified in Cosmic or the MutDB databases. The variant was identified in control databases in 6664 of 282864 chromosomes (112 homozygous) at a frequency of 0.02, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 363 of 10370 chromosomes (freq: 0.04), European (Non-Finnish) in 3775 of 129186 chromosomes (freq: 0.03), Other in 200 of 7226 chromosomes (freq: 0.03), South Asian in 815 of 30616 chromosomes (freq: 0.03), European (Finnish) in 499 of 25118 chromosomes (freq: 0.02), African in 421 of 24958 chromosomes (freq: 0.02), Latino in 589 of 35440 chromosomes (freq: 0.02), and East Asian in 2 of 19950 chromosomes (freq: 0.0001). The p.Thr1100= 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 addition, 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. -

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
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.0
DANN	Benign	0.64

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: rs45516100; hg19: chr16-23619235; COSMIC: COSV55161892;