rs754660432

Variant names:

• chr16-23630471-T-C
• rs754660432
• NM_024675.4:c.1685-2A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-23630471-T-C
• chr16-23630471-T-G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_024675.4(PALB2):​c.1685-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000414 in 1,450,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PALB2 NM_024675.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.22
• Publications: 6 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 16-23630471-T-C is Pathogenic according to our data. Variant chr16-23630471-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 449968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1685-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 12	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1685-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 12	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 237008 AF XY: 0.00000776

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: 0.00000952

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1450498 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 721596

African (AFR) AF: 0.00 AC: 0 AN: 33168

American (AMR) AF: 0.00 AC: 0 AN: 43926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 85302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1103982

Other (OTH) AF: 0.00 AC: 0 AN: 60028

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 4 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs754660432, gnomAD 0.001%). Disruption of this splice site has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 26534844, 28664506). This variant is also known as c.1691-2A>G. ClinVar contains an entry for this variant (Variation ID: 449968). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 34846068; internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Sep 11, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

PALB2-related disorder Pathogenic:1

Jan 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.1685-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant (also reported as c.1691-2A>G) was reported in individuals with a history of breast and/or ovarian cancer (Family 50, Table 1, Li et al. 2016. PubMed ID: 26534844; Table 1, Yang et al. 2017. PubMed ID: 28664506). Functional studies have also confirmed this variant impacts splicing (Table 1, Valenzuela-Palomo et al. 2021. PubMed ID: 34846068) This variant is reported in 0.00095% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23641792-T-C). In ClinVar, this variant is interpreted as likely pathogenic by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/449968/). Variants that disrupt the consensus splice acceptor site in PALB2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

May 16, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used: PVS1, PS4_Moderate -

not provided Pathogenic:1

May 16, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted PALB2 c.1685-2A>G or IVS4-2A>G and consists of an A>G nucleotidesubstitution at the -2 position of intron 4 of the PALB2 gene. This variant destroys a canonical splice acceptor site andis predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one individual witha personal and family history of breast and/or ovarian cancer (Li 2016). Based on the currently available information,we consider PALB2 c.1685-2A>G to be a likely pathogenic variant -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 15, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1685-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 5 in the PALB2 gene. This alteration was reported in one familial breast cancer cohort of 660 BRCA1/2 negative women undergoing 17 gene panel testing (Li J et al. J Med Genet, 2016 Jan;53:34-42). This alteration was also reported in a patient diagnosed with triple-negative breast cancer at age 49 (Yang XR et al. Breast Cancer Res Treat, 2017 Oct;165:687-697). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Valenzuela-Palomo A et al. J Pathol, 2022 03;256:321-334, Ambry internal data). Of note, this alteration is also designated as c.1691-2A>G in the published literature. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Benign	0.92
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		4.2
GERP RS		4.3
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
Splicevardb		3.0
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs754660432; hg19: chr16-23641792;