16-23621357-C-G

Variant names:

• chr16-23621357-C-G
• rs876659463
• NM_024675.4:c.3113+5G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_024675.4(PALB2):​c.3113+5G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000816 in 1,594,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: PALB2 NM_024675.4 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 4.74

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]

ENSG00000261723 (HGNC:58305):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 16-23621357-C-G is Pathogenic according to our data. Variant chr16-23621357-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 231961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23621357-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3113+5G>C		splice_region_variant, intron_variant	Intron 10 of 12	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3113+5G>C		splice_region_variant, intron_variant	Intron 10 of 12	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 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

GnomAD4 exome AF: 0.00000832 AC: 12 AN: 1441898 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 8 AN XY: 718778

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000110

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Nov 07, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.3113+5G>C variant has been reported in the published literature in individuals with breast cancer (PMID: 23824750 (2014)), pancreatic cancer (PMID: 19264984 (2009)), and ovarian cancer (PMID: 29053726 (2017)). This variant has also been identified in an individual with Fanconi Anemia who also carried a pathogenic PALB2 variant (PMID: 17200671 (2017)). Assessment of experimental evidence suggests this variant results in abnormal RNA splicing (PMID: 31642931 (2019), 30890586 (2019), 32133419 (2020), 34846068 (2022)). The frequency of this variant in the general population, 0.0000066 (1/152190 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper PALB2 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic. -

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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 11, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published RNA studies demonstrate aberrant splicing resulting in a predicted null allele in the majority of transcripts (PMID: 30890586, 31642931, 32133419, 34846068); Reported with a second truncating variant in PALB2 in an individual with Fanconi Anemia (PMID: 17200671); Observed in individuals with personal and/or family history of breast or ovarian cancer (PMID: 24415441, 23824750, 29053726, 29522266); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21165770, 24415441, 23824750, 19264984, 25525159, 31642931, 32133419, 32546565, 24485656, 20871615, 19609323, 30890586, 29522266, 37506692, 37651980, 38476606, 34846068, 17200671, 29053726) -

Oct 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.3113+5G>C variant (rs876659463, ClinVar Variation ID: 231961) is reported in the literature in heterozygous individuals affected with breast and/or ovarian cancer (Harter 2017, Song 2021, Wong-Brown 2014) and in an individual who also carried a pathogenic variant in trans affected with Fanconi anemia subtype FA-N (Reid 2007). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This is an intronic variant and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby donor splice site. In addition, a minigene assay demonstrated that the mutant allele only produced minimal amounts of wild type length transcript (Valenzuela-Palomo 2022). Based on available information, this variant is considered to be pathogenic. References: Harter P et al. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). PLoS One. 2017 Oct 20;12(10):e0186043. PMID: 29053726. Reid S et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007 Feb;39(2):162-4. PMID: 17200671. Song H et al. Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer. J Med Genet. 2021 May;58(5):305-313. PMID: 32546565. Valenzuela-Palomo A et al. Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants. J Pathol. 2022 Mar;256(3):321-334. PMID: 34846068. Wong-Brown MW et al. Low prevalence of germline PALB2 mutations in Australian triple-negative breast cancer. Int J Cancer. 2014 Jan 15;134(2):301-5. PMID: 23824750. -

May 13, 2019

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:3

Oct 22, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 10 of the PALB2 gene. It does not directly change the encoded amino acid sequence of the PALB2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer or Fanconi anemia (PMID: 17200671, 23824750, 24415441). ClinVar contains an entry for this variant (Variation ID: 231961). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exons 9 and 10 or activation of a cryptic splice site in exon 10, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 17200671, 30890586; internal data). For these reasons, this variant has been classified as Pathogenic. -

Oct 06, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 30890586, 32133419, Myriad internal data]. This variant has been observed in trans with a known pathogenic variant in one or more individuals with Fanconi Anemia [PMID: 17200671]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Apr 05, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3113+5G>C intronic variant results from a G to C substitution five nucleotides after coding exon 10 in the PALB2 gene. This alteration was reported in one parent of an individual with a clinical diagnosis of Fanconi anemia (FA), who was presumed to be compound heterozygous for c.3113+5C>G and c.395delT (Reid S et al. Nat. Genet. 2007 Feb; 39(2):162-4). This alteration has also been reported in one individual from a cohort of patients evaluated for familial breast cancer and in one individual with triple negative breast cancer at age 54 from an unselected cohort of women with triple negative breast cancer (Fernandes PH et al. Cancer. 2014 Apr; 120(7):963-7; Wong-Brown MW et al. Int. J. Cancer. 2014 Jan; 134(2):301-5). The study authors considered this alteration to be a disease causing mutation, and predicted that this alteration produces a frameshift that results in a protein truncation; however, direct evidence was not provided. Of note, this alteration is also designated as IVS10+5G>C in some published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on nucleotide sequence alignment, this position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing (Ambry internal data; Lopez-Perolio I et al. J. Med. Genet. 2019 Jul;56:453-460). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Dec 06, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to C nucleotide substitution at the +5 position of intron 10 of the PALB2 gene. It is also known as IVS10+5G>C in the literature. RNA studies have shown that this variant causes skipping of exon 9 and 10 (PMID: 17200671), deletion of the last 31 nucleotides of exon 10 (PMID: 30890586), or skipping of exon 10 (PMID: 32133419) in the RNA transcripts. These aberrant transcripts are expected to result in an absent protein product or disrupted functional domains in the PALB2 protein. In a mini-gene assay, only 4.9% of the transcripts produced from the mutant allele showed normal length (PMID: 34846068). This variant has been observed in individuals affected with breast cancer (PMID: 23824750, 24415441). This variant has also been observed in the heterozygous state in a parent of an individual who is affected with Fanconi anemia and presumed to have this variant in trans with another PALB2 pathogenic variant (PMID: 17200671, 19264984). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

Jan 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 36
DS_DL_spliceai		0.46		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs876659463; hg19: chr16-23632678;