16-23603525-C-T

Variant names:

• chr16-23603525-C-T
• rs45439097
• NM_024675.4:c.3495G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_024675.4(PALB2):​c.3495G>A​(p.Ser1165Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1165S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: -0.209
• Publications: 11 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 16-23603525-C-T is Benign according to our data. Variant chr16-23603525-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.209 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3495G>A	p.Ser1165Ser	synonymous_variant	Exon 13 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3495G>A	p.Ser1165Ser	synonymous_variant	Exon 13 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000620 AC: 156 AN: 251484 AF XY: 0.000647

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00142 AC: 2070 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00138 AC XY: 1000 AN XY: 727232

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00175 AC: 1947 AN: 1111974

Other (OTH) AF: 0.00118 AC: 71 AN: 60396

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74354

African (AFR) AF: 0.00130 AC: 54 AN: 41486

American (AMR) AF: 0.000328 AC: 5 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00117

EpiCase AF: 0.00185

EpiControl AF: 0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:11

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALB2: BP4, BP7 -

May 13, 2019

Leiden Open Variation Database

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 18, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.3495G>A variant affects a non-conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts damaging outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however, it may strengthen a cryptic 5' splicing donor site. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 89/125390 control chromosomes at a frequency of 0.0007098, which is about 5 times of the maximal expected frequency of a pathogenic allele (0.0001563), suggesting this variant is benign. In addition, mutliple clinical laboratories/reputable databases/literatures classified this variant as benign/polymorphism. Taken together, this variant was classified as benign. -

Jun 24, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Jun 23, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 21, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

May 03, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 25, 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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Benign:3

May 15, 2022

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALB2:c.3495G>A is present in 0.070% in the large population studies (GnomAd). The deep exonic variant is predicted to create a de novo donor splice site in the last exon (exon 13) of PALB2 by in silico splicing tools. Functional RNA study has shown that the variant does not cause splicing aberration (PMID: 35806449). Therefore the variant was classified as likely benign (ACMG/AMP: BS3-Stand alone, BS1, PP3). -

Jan 22, 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. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group N Benign:2

Apr 28, 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. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 p.Ser1165Ser variant was identified in 19 of 8732 proband chromosomes (frequency: 0.002) from individuals or families with breast or pancreatic cancer and was present in 11 of 4896 control chromosomes (frequency: 0.002) from healthy individuals (Papi_2010_19763884, Ding_2011_20927582, Bogdanova_2011_21165770, Hellebrand_2011_21618343, Nguyen-Dumont_2013_24206657, Thompson_2015_26283626, Aoude_2014_24949998, Zhen_2015_25356972). The variant was also identified in dbSNP (ID: rs45439097) as “With other allele”, ClinVar (2x as benign by GeneDx, Invitae, 5x as likely benign by Ambry Genetics, Prevention Genetics, Illumina Clinical services, Quest Diagnostics, PALB2 database), Clinvitae (4x, as benign and likely benign by ClinVar), LOVD 3.0 (6x reported) and Zhejiang Colon Cancer Database (1x. The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 192 of 277176 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 29 of 24016 chromosomes (freq: 0.0012), other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 11 of 34420 chromosomes (freq: 0.0003), European Non-Finnish in 149 of 126698 chromosomes (freq: 0.0012), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In addition the variant was identified by our laboratory in 1 individual with breast and skin cancer with a co-occurring pathogenic BRCA2 variant (c.8904delC p.Val2969CysfsX7), increasing the likelihood that the p.Ser1165Ser variant does not have clinical significance. The p.Ser1165Ser 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

PALB2-related disorder Benign:1

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Breast and/or ovarian cancer Benign:1

Apr 26, 2023

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

Significance: Likely 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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 p.Ser1165Ser variant was identified in 19 of 8732 proband chromosomes (frequency: 0.002) from individuals or families with breast or pancreatic cancer and was present in 11 of 4896 control chromosomes (frequency: 0.002) from healthy individuals (Papi_2010_19763884, Ding_2011_20927582, Bogdanova_2011_21165770, Hellebrand_2011_21618343, Nguyen-Dumont_2013_24206657, Thompson_2015_26283626, Aoude_2014_24949998, Zhen_2015_25356972). The variant was also identified in dbSNP (ID: rs45439097) as “With other allele”, ClinVar (2x as benign by GeneDx, Invitae, 5x as likely benign by Ambry Genetics, Prevention Genetics, Illumina Clinical services, Quest Diagnostics, PALB2 database), Clinvitae (4x, as benign and likely benign by ClinVar), LOVD 3.0 (6x reported) and Zhejiang Colon Cancer Database (1x. The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 192 of 277176 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 29 of 24016 chromosomes (freq: 0.0012), other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 11 of 34420 chromosomes (freq: 0.0003), European Non-Finnish in 149 of 126698 chromosomes (freq: 0.0012), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In addition the variant was identified by our laboratory in 1 individual with breast and skin cancer with a co-occurring pathogenic BRCA2 variant (c.8904delC p.Val2969CysfsX7), increasing the likelihood that the p.Ser1165Ser variant does not have clinical significance. The p.Ser1165Ser 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.9
DANN	Benign	0.72
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs45439097; hg19: chr16-23614846;