16-23635621-T-C

Variant names:

• chr16-23635621-T-C
• rs3809683
• NM_024675.4:c.925A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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. I309M) has been classified as Likely benign.

• 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:22 O:1
• Conservation: PhyloP100: -4.29
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 13 benign, 31 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 Benign/Likely_benign. ClinVar VariationId is 126780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.925A>G	p.Ile309Val	missense	Exon 4 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.865A>G	p.Ile289Val	missense	Exon 3 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.925A>G	p.Ile309Val	missense	Exon 4 of 12	NP_001394226.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.925A>G	p.Ile309Val	missense	Exon 4 of 13	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.40A>G	p.Ile14Val	missense	Exon 4 of 13	ENSP00000454703.2
	PALB2	ENST00000561514.3	TSL:5	c.931A>G	p.Ile311Val	missense	Exon 4 of 13	ENSP00000460666.3

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

GnomAD2 exomes AF: 0.00285 AC: 717 AN: 251174 AF XY: 0.00213

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 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

African (AFR) AF: 0.0303 AC: 1014 AN: 33474

American (AMR) AF: 0.00179 AC: 80 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00630 AC: 250 AN: 39684

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111956

Other (OTH) AF: 0.00240 AC: 145 AN: 60386

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

African (AFR) AF: 0.0279 AC: 1160 AN: 41594

American (AMR) AF: 0.00346 AC: 53 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0121 AC: 63 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00347 Hom.: 17

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:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7 Other:1

Nov 01, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 06, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:5

Dec 10, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 11, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 24, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 12, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Dec 28, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 13, 2019

Leiden Open Variation Database

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke, Yukihide Momozawa.

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Familial cancer of breast Benign:3

Jun 01, 2015

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: case-control

Jan 10, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group N Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.83	N
PhyloP100		-4.3
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	0.95	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs3809683; hg19: chr16-23646942; COSMIC: COSV55164135; COSMIC: COSV55164135;