chr16-23636336-T-C

Position:

chr16-23636336-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_024675.4(PALB2):c.212-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,586,880 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PALB2
NM_024675.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 3.12

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:

PALB2 (HGNC:):

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.41336703 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of -36, new splice context is: tttttgttttattttataAGaaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 16-23636336-T-C is Pathogenic according to our data. Variant chr16-23636336-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.212-2A>G		splice_acceptor_variant, intron_variant		ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.212-2A>G		splice_acceptor_variant, intron_variant		1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000452

AC:

AN:

221342

Hom.:

AF XY:

0.00

AC XY:

AN XY:

120012

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:

0.0000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1434974

Hom.:

Cov.:

AF XY:

0.00000421

AC XY:

AN XY:

713020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000238

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:

0.00000274

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151906

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2024	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 30293905, 32172797, 35626031, 26681312, 38061684, 30890586) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 26, 2021	This test has identified one copy of the c.212-2A>G variant in the PALB2 gene. This variant is located in a canonical splice-acceptor site and interferes with normal PALB2 mRNA splicing. The variant has been reported in an individual with breast cancer in the published literature (PMID: 26681312 (2015)). Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 30, 2022	- -

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change affects an acceptor splice site in intron 3 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 (rs730881879, gnomAD 0.001%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182757). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30890586; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 17, 2015	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2024	The c.212-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the PALB2 gene. This alteration has been identified in multiple individuals with a personal history of breast and/or ovarian cancer (Susswein LR et al. Genet. Med. 2016 08;18:823-32; Espinel W et al. Cancers (Basel), 2022 May;14:). 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 and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 11, 2021	This variant causes an A>G nucleotide substitution at the -2 position of intron 3 of the PALB2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A minigene splicing assay reported that a similar canonical splice acceptor site variant in intron 3, c.212-1G>A, resulted in the out-of-frame skipping of exon 4 and exon 5 (PMID: 30890586). This variant has been reported in an individual affected with breast cancer (PMID: 26681312). This variant has been identified in 1/221342 chromosomes 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. -

PALB2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2024

The PALB2 c.212-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in patients with a personal history of breast and/or ovarian cancer (Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table S2, Espinel et al. 2022. PubMed ID: 35626031; Infante et al. 2024. PubMed ID: 38061684). Of note, a minigene splicing assay has shown that a similar canonical splice acceptor site variant c.212-1G>A leads to a skipping of exon 4 and 5 (Lopez-Perolio et al. 2019. PubMed ID: 30890586). The c.212-2A>G variant is reported in 0.0010% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has been interpreted as likely pathogenic and pathogenic by multiple labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/182757/). Variants that disrupt the consensus splice acceptor site in PALB2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 05, 2021

- -

Fanconi anemia complementation group N

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 10, 2019

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 31, 2024

Variant summary: PALB2 c.212-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of PALB2 function. Several computational tools predict a significant impact on normal splicing: All predict the variant abolishes the canonical 3' acceptor site. At least one publication reports experimental evidence that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product (PMID 30890586). The variant allele was found at a frequency of 4.5e-06 in 221342 control chromosomes. c.212-2A>G has been reported in the literature in at-least two individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Susswein_2015, Espinel_2022). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35626031, 26681312, Internal data). ClinVar contains an entry for this variant (Variation ID: 182757). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Benign

0.96

Eigen

Pathogenic

0.85

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.35

Position offset: -34

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

Other links and lift over