chr16-23626372-T-C

Variant names:

• chr16-23626372-T-C
• rs515726090
• NM_024675.4:c.2612A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_024675.4(PALB2):​c.2612A>G​(p.Asp871Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D871V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:13
• Conservation: PhyloP100: 5.04
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

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.2612A>G	p.Asp871Gly	missense	Exon 7 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.2552A>G	p.Asp851Gly	missense	Exon 6 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.2540A>G	p.Asp847Gly	missense	Exon 6 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.2612A>G	p.Asp871Gly	missense	Exon 7 of 13	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.1727A>G	p.Asp576Gly	missense	Exon 7 of 13	ENSP00000454703.2
	PALB2	ENST00000561514.3	TSL:5	c.2618A>G	p.Asp873Gly	missense	Exon 7 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251488 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

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

American (AMR) AF: 0.00 AC: 0 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: 0.0000232 AC: 2 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:5

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 871 of the PALB2 protein (p.Asp871Gly). This variant is present in population databases (rs515726090, gnomAD 0.006%). This missense change has been observed in individual(s) with breast, pancreatic and colorectal cancer (PMID: 22692731, 25452441, 32658311, 32885271, 33980423, 34371384). ClinVar contains an entry for this variant (Variation ID: 126670). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395, 31757951). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

May 09, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 31, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

Jan 22, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 13, 2019

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

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

Hereditary cancer-predisposing syndrome Uncertain:4

Nov 15, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Apr 01, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glycine at codon 871 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have reported that this variant has no impact on PALB2 function in homology-directed repair, checkpoint response and sensitivity to cisplatin and PARP inhibitors assays (PMID: 31636395, 31757951). This variant has been reported in individuals affected with breast cancer and unaffected individuals, and it also has been reported in a breast cancer case-control meta-analysis in 2/60466 cases and 3/53461 unaffected individuals (PMID: 22692731, 25452441, 32885271, 33471991, 33980423; Leiden Open Variation Database DB-ID PALB2_010115). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 34371384). This variant has been identified in 4/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Apr 27, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP1, PP3 c.2612A>G, located in exon 7 of the PALB2 gene, is predicted to result in the substitution of leucine by histidine at codon 871, p.(Asp871Gly)(BP1). The variant allele was found in 4/268356 alleles, with a filter allele frequency of 0.001% at 95% confidence, within the South Asian population in the gnomAD v2.1.1 database (non-cancer data set). The SpliceAI algorithm predicts that the variant impairs the splicing acceptor site of intron 6 (deltascore: 0.28 (acceptor gain) and 0.21(acceptor loss))(PP3). It has been reported in ClinVar (12x uncertain significance) and LOVD (2x uncertain significance, 4x not classified) databases. Functional studies has been reported for this variant (PMID: 31636395, 33195396); however, following ClinGen VCEP recommendation, this information cannot be used for variant classification because functional studies have not been validated for PALB2 gene. Based on currently available information, c.2612A>G is classified as an uncertain significance variant according to ClinGen-PALB2 Guidelines version v1.0.0.

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D871G variant (also known as c.2612A>G), located in coding exon 7 of the PALB2 gene, results from an A to G substitution at nucleotide position 2612. The aspartic acid at codon 871 is replaced by glycine, an amino acid with similar properties. This alteration was detected in a cohort of 1824 patients with triple negative breast cancer who were unselected for family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11), in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 Mar;147(3):871-879) and in 1/189 colorectal cancer patients and in none of the cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer. 2021 01;148(2):285-295). This alteration was also reported in an Ashkenazi Jewish female diagnosed with breast cancer at age 50; her mother, two maternal aunts, and maternal grandmother were also diagnosed with breast cancer. The alteration was not detected in 113 Ashkenazi cancer-free controls (Catucci I et al. Fam. Cancer. 2012 Sep;11:483-91). This alteration was found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). This alteration was also evaluated in another functional study, and was found to be functionally normal in a homology-directed DNA repair (HDR) assay, and in a PARP inhibitor sensitivity assay (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

not provided Uncertain:2

Jun 08, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Observed in individuals with breast and/or ovarian cancer (Catucci 2012, Couch 2015); Published functional studies demonstrate homology-directed repair (HDR) activity, protein stability, and maintenance of the G2/M checkpoint similar to wild type (Boonen 2019, Wiltshire 2020); This variant is associated with the following publications: (PMID: 25452441, 22692731, 19609323, 20871615, 24485656, 31757951, 31636395)

Nov 18, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.2612A>G (p.Asp871Gly) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 22692731 (2012), 25452441 (2015), 32885271 (2021), 33980423 (2021)), pancreatic cancer (PMID: 34371384 (2021)), and colorectal cancer (PMID: 32658311 (2021)). This variant has been identified in an individual with Fanconi anemia who also carried a pathogenic variant in the FANCA gene (PMID: 37865086 (2023)). In a large case-control study, this variant was observed in additional individuals with breast cancer as well as in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). Experimental studies indicate this variant has neutral effects on PALB2 protein functions (PMIDs: 31757951 (2019), 31636395 (2020)). The frequency of this variant in the general population, 0.000016 (4/251488 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1

Jul 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast 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.Asp871Gly variant was identified in 2 of 3840 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer and was not identified in 226 control chromosomes from healthy individuals (Catucci 2012, Couch 2015). The variant was also identified in dbSNP (ID: rs515726090), ClinVar (classified as uncertain significance by Invitae, PALB2 database), Clinvitae (classified as uncertain significance by Invitae), LOVD 3.0 (2X), databases. The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 4 of 246266 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: European Non-Finnish in 2 of 111718 chromosomes (freq: 0.000018), and SouthAsian in 2 of 30782 chromosomes (freq: 0.000065); it was not observed in the African, “Other”, Latino, AshkenaziJewish, EastAsian, EuropeanFinnish, populations. The p.Asp871 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.68		Loss of helix (P = 0.0376)
MVP		0.81
MPC		0.39
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.90
gMVP		0.67
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 0
DS_AL_spliceai		0.21		Position offset: 25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs515726090; hg19: chr16-23637693;