NM_024675.4:c.1544A>G

Variant names:

• chr16-23635002-T-C
• rs515726072
• NM_024675.4:c.1544A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_024675.4(PALB2):​c.1544A>G​(p.Lys515Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K515E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:9
• Conservation: PhyloP100: 0.402
• Publications: 13 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12248054).
• BP6: Variant 16-23635002-T-C is Benign according to our data. Variant chr16-23635002-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126607.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1544A>G	p.Lys515Arg	missense_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1544A>G	p.Lys515Arg	missense_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000915 AC: 23 AN: 251486 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.0000564 AC XY: 41 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000179 AC: 8 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: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1112012

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:3

Aug 25, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP1 c.1544A>G, located in exon 4 of the PALB2 gene, is predicted to result in the substitution of lysine with arginine at codon 515, p.(Lys515Arg). The SpliceAI algorithm predicts no significant impact on splicing, and there is a very low likelihood that missense variants are pathogenic in PALB2 (BP1). This variant is found in 22/268354 alleles at a frequency of 0.008% in the gnomAD v2.1.1 database, non-cancer dataset. This variant was tested in a high-throughput cell-based functional assay, showing a slight homologous recombination reduction compared to wild type, and total PARPi resistance (PMID: 31757951). This variant has been reported in multiple cancer-affected patients (PMID: 29052111, 37686625, 26283626, 25503501, 31159747, 29522266, 28729728). It has been found in 9 out of 60466 breast cancer cases and 7 of the 53461 healthy controls in a case-control study (PMID: 33471991). This variant has been reported in the ClinVar database (1x benign, 8x likely benign, 10x uncertain significance) and in LOVD (2x likely benign, 1x uncertain significance). Based on the currently available evidence, c.1544A>G is classified as an uncertain significance variant according to ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.1.0.

Jan 06, 2022

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 21, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 28, 2018

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.

Familial cancer of breast Uncertain:2 Benign:3

Jan 14, 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 in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 04, 2019

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz.

Jul 22, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2015

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: case-control

not provided Uncertain:2 Benign:2

Sep 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27328445, 29052111, 29338072, 26283626, 22241545, 21618343, 27616075, 25503501, 27930734, 21356067, 28873162, 27997549, 29522266, 31757951, 31159747)

Mar 13, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.1544A>G (p.Lys515Arg) variant has been reported in the published literature in several affected individuals with breast and/or ovarian cancer (PMIDs: 26283626 (2015), 27616075 (2016), 28873162 (2017), 29052111 (2018), 29522266 (2018), and 32658311 (2021)). It has also been found in reportedly healthy controls individuals (PMID: 21618343 (2011)). It was also reported in breast cancer cases as well as in reportedly healthy individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)).A functional study showed minimal reduction in HR activity and no effect on PARPi sensitivity compared to wild-type (PMID: 31757951 (2019)). The frequency of this variant in the general population, 0.0002 (7/35438 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALB2: PS3:Supporting, BP1, BP4

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:2

Mar 13, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PALB2 c.1544A>G (p.Lys515Arg) results in a conservative amino acid change located in the DNA-binding domain (DBD, Nepomuceno_2020) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.3e-05 in 257362 control chromosomes, predominantly at a frequency of 0.0002 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), suggesting the variant may be a benign polymorphism found in the Latino subpopulation. c.1544A>G has been reported in the literature in individuals affected with cancer including Hereditary Breast and Ovarian Cancer and stomach adenocarcinoma but it was also reported in one healthy woman older than 50 years (Hauke_2018, He_2016, Hellebrand_2011, Kraus_2016, Lu_2015, Mandelker_2017, Maxwell_2014, Myszka_2017, Thompson_2015, Tischkowitz_2012, Tsaousis_2019, Akcay_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Moreover, the variant was reported in the FLOSSIES database in two women older than age 70 years who have never had cancer, providing supporting evidence for a benign role. One co-occurrence with a pathogenic variant has been reported internally (APC c.4873delC, p.Gln1625fs*25; internal LCA database). At least one functional study reports this variant has slightly reducing HR activity and no effect on PARPi sensitivity compared to WT (Boonen_2019). Twelve ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=9) and as likely benign (n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: Ingen andre kriterier kan anvendes end BP1.

PALB2-related disorder Uncertain:1

Apr 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 c.1544A>G variant is predicted to result in the amino acid substitution p.Lys515Arg. This variant has been previously reported in individuals with familial breast cancer (Thompson et al 2015. PubMed ID: 26283626; Kraus et al 2017. PubMed ID: 27616075). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD and in ClinVar it is classified as likely benign and a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/126607/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Breast and/or ovarian cancer Uncertain:1

Nov 02, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial ovarian cancer Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 p.Lys515Arg variant was identified in 6 of 10468 proband chromosomes (frequency: 0.00057) from individuals or families with breast or ovarian cancer and was not identified in 4896 control chromosomes from healthy individuals (Hellebrand 2011, Kraus 2017, Maxwell 2015, Myszka 2017, Thompson 2015, Tischkowitz 2012). The variant was also identified in dbSNP (ID: rs515726072) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, Genedx, PALB2 database and three clinical laboratories), MutDB , and in LOVD 3.0 (1x), databases. The variant was not identified in Cosmic, or Zhejiang University Database. The variant was identified in control databases in 23 of 277248 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6468 chromosomes (freq: 0.00016), Latino in 7 of 34418 chromosomes (freq: 0.0002), European in 15 of 126730 chromosomes (freq: 0.00012), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys515 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Hereditary cancer Benign:1

Sep 11, 2024

Mendelics

Significance: Likely 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: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;L
PhyloP100		0.40
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.0
Sift	Benign	0.072	T;T
Sift4G	Benign	0.16	T;T
Vest4		0.11
ClinPred		0.047	T
GERP RS		3.3
Varity_R		0.054
gMVP		0.14
Mutation Taster		=94/6	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: rs515726072; hg19: chr16-23646323;