16-23635621-T-C

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.925A>G(p.Ile309Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,148 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. I309R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0085 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (20 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: -4.29

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 -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 5 benign, 16 uncertain in NM_024675.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.002647072).
• BP6: Variant 16-23635621-T-C is Benign according to our data. Variant chr16-23635621-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 126780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635621-T-C is described in Lovd as [Likely_benign]. Variant chr16-23635621-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00854 (1301/152364) while in subpopulation AFR AF= 0.0279 (1160/41594). AF 95% confidence interval is 0.0266. There are 20 homozygotes in gnomad4. There are 603 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.925A>G	p.Ile309Val	missense_variant	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.925A>G	p.Ile309Val	missense_variant	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.00851 AC: 1296 AN: 152246 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0279

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00285 AC: 717 AN: 251174 Hom.: 10 AF XY: 0.00213 AC XY: 289 AN XY: 135796

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00968

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00106 AC: 1551 AN: 1461784 Hom.: 20 Cov.: 32 AF XY: 0.000875 AC XY: 636 AN XY: 727190

Gnomad4 AFR exome AF: 0.0303

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00630

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00854 AC: 1301 AN: 152364 Hom.: 20 Cov.: 32 AF XY: 0.00809 AC XY: 603 AN XY: 74524

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0121

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00194 Hom.: 9

Bravo AF: 0.0105

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0287 AC: 126

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7 Other:1

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	GeneDx	Nov 01, 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, 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	Apr 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	- -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 10, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 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:2

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, Yukihide Momozawa. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 28, 2022	- -

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	Invitae	Feb 01, 2024	- -

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

- -

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.Ile309Val variant was identified in 41 of 4986 proband chromosomes (frequency: 0.008) from individuals or families with breast Cancer of African-American, Chinese, Malaysian and Singaporean descent and was present in 50 of 4390 control chromosomes (frequency: 0.011) from healthy individuals (Ding 2011, Li 2015, Phuah 2013, Wong-Brown 2014, Zheng 2012, Sluiter 2009). The variant was also identified in dbSNP (ID: rs3809683) as “Other”, ClinVar (benign by GeneDx, Ambry Genetics, Invitae), PALB2 Database (likely benign by Cancer Genetics Laboratory and Illumina Clinical Services Laboratory), LOVD 3.0 (8x with no classification) Zhejiang Colon Cancer Database (1x as unknown). The variant was not identified in Cosmic, MutDB, databases. The variant was further identified in the 1000 Genomes Project in 58 of 5000 chromosomes (freq. 0.01) and the NHLBI GO Exome Sequencing Project in 126 of 4394 African American alleles (freq. 0.03). The variant was identified in control databases in 932 of 277056 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Notably the variant was identified in the African population in 690 of 24026 chromosomes (freq. 0.02) including 10 homozygous individuals. The p.Ile309 residue is not conserved in mammals and the variant amino acid (Val) is present in Macaca mulatta, Rattus norvegicus, and Mus musculus increasing the likelihood that this variant does not have clinical significance. In addition, 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 is 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
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.0010
Dann	Benign	0.11
DEOGEN2	Benign	0.0051	T;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.17	N;N
Sift	Benign	1.0	T;T
Sift4G	Benign	0.95	T;T
Polyphen		0.0	.;B
Vest4		0.050
MVP		0.11
MPC		0.046
ClinPred		0.0029	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.026
gMVP		0.079

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3809683; hg19: chr16-23646942; COSMIC: COSV55164135; COSMIC: COSV55164135;