Variant rs754660432 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PP3_ModeratePP5_Very_Strong

The NM_024675.4(PALB2):c.1685-2A>G variant causes a splice acceptor 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

Scores

Splicing: ADA: 0.9999

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.22

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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 id is 449968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.1685-2A>G		splice_acceptor_variant		ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.1685-2A>G		splice_acceptor_variant		1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000422

AC:

AN:

237008

Hom.:

AF XY:

0.00000776

AC XY:

AN XY:

128922

show subpopulations

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 SAS 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:

AN:

1450498

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721596

show subpopulations

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:

0.00000543

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	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 disrupted 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; Invitae). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 11, 2023	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

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2023

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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2018

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

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

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Benign

0.92

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.88

MutationTaster

Benign

1.0

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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