16-23603456-AACTTATGAATAGTGGTATACAAATATATTTCCATCTTTTTGTCCAGCCAGCAAATGAGAGTCTGTACCCGACCATTTCACAAAAGACCAATGTTGGTCAGAGACAGGTGGGAGGAGGGCAGTACACTGACCGAGAAGTAAGTCCCAAATGGCAATTGTTCCAGAAGTCAAGATTGCTGCTGCACAGTGATCTTTCACGTCACCTTCCAGGAACCTGATAGCATACAAAGAAGATATAATTCAGATTACATATCCAAAAAACAATTAAAAAAAAAAAAAAGGTCAAAACCATGTTCCCAAAACCAGCAACAGGAACAAAAATCCCTGTAACTATGAATGCCTACATTTGTAGCCTTAGAGGTCT-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024675.4(PALB2):c.3351-150_*2del variant causes a splice acceptor, coding sequence, 3 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 splice_acceptor, coding_sequence, 3_prime_UTR, intron
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23603456-AACTTATGAATAGTGGTATACAAATATATTTCCATCTTTTTGTCCAGCCAGCAAATGAGAGTCTGTACCCGACCATTTCACAAAAGACCAATGTTGGTCAGAGACAGGTGGGAGGAGGGCAGTACACTGACCGAGAAGTAAGTCCCAAATGGCAATTGTTCCAGAAGTCAAGATTGCTGCTGCACAGTGATCTTTCACGTCACCTTCCAGGAACCTGATAGCATACAAAGAAGATATAATTCAGATTACATATCCAAAAAACAATTAAAAAAAAAAAAAAGGTCAAAACCATGTTCCCAAAACCAGCAACAGGAACAAAAATCCCTGTAACTATGAATGCCTACATTTGTAGCCTTAGAGGTCT-A is Pathogenic according to our data. Variant chr16-23603456-AACTTATGAATAGTGGTATACAAATATATTTCCATCTTTTTGTCCAGCCAGCAAATGAGAGTCTGTACCCGACCATTTCACAAAAGACCAATGTTGGTCAGAGACAGGTGGGAGGAGGGCAGTACACTGACCGAGAAGTAAGTCCCAAATGGCAATTGTTCCAGAAGTCAAGATTGCTGCTGCACAGTGATCTTTCACGTCACCTTCCAGGAACCTGATAGCATACAAAGAAGATATAATTCAGATTACATATCCAAAAAACAATTAAAAAAAAAAAAAAGGTCAAAACCATGTTCCCAAAACCAGCAACAGGAACAAAAATCCCTGTAACTATGAATGCCTACATTTGTAGCCTTAGAGGTCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1048983.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3351-150_*2del		splice_acceptor_variant, coding_sequence_variant, 3_prime_UTR_variant, intron_variant	13/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3351-150_*2del		splice_acceptor_variant, coding_sequence_variant, 3_prime_UTR_variant, intron_variant	13/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of breast Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The PALB2 c.3202-?_3561+?del variant (chr:16 g.23614779_23619332del GRCh37) results in an in-frame deletion of exons 12-13, although the precise breakpoints of this deletion were not determined nor were the effects of this variant on the resulting mRNA or protein product determined. The variant was identified in a patient with breast and pancreas cancer (at ages 47 and 61 respectively) and whose mother died of pancreas cancer at age 83 (Tischkowitz 2009). The variant was not identified in dbSNP, ClinVar, LOVD 3.0, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-23614777;