rs587776405

Variant names:

• chr16-23641110-C-T
• rs587776405
• NM_024675.4:c.48G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_024675.4(PALB2):​c.48G>A​(p.Lys16Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000665419: "In one assay using lymphoblastoid cell lines from a patient with the c.48G>A alteration, the canonical donor splice site was abolished and an alternative splice site was used resulting in an aberrant transcript and a premature termination codon." PMID:25170841" and additional evidence is available in ClinVar. The gene PALB2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.38
• Publications: 4 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: Ambry Genetics
• PALB2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for PALB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000665419: "In one assay using lymphoblastoid cell lines from a patient with the c.48G>A alteration, the canonical donor splice site was abolished and an alternative splice site was used resulting in an aberrant transcript and a premature termination codon." PMID:25170841; SCV001354215: Functional RNA studies have shown that this variant causes loss of the canonical donor site of intron 1, resulting in use of an upstream cryptic donor site and a transcript that lacks 17 nucleotides at the 3′ end of exon 1. PMID 24556926, 25099575; SCV001229787: Studies have shown that this variant results in activation of cryptic splice sites and introduces a premature termination codon (PMID: 24556926; Invitae).; SCV004188435: mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 24556926].; SCV005415956: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-23641110-C-T is Pathogenic according to our data. Variant chr16-23641110-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 143978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.48G>A	p.Lys16Lys	splice_region synonymous	Exon 1 of 13	NP_078951.2
	PALB2	NM_001407305.1		c.-972G>A		splice_region	Exon 1 of 14	NP_001394234.1	H3BN63
	PALB2	NM_001407307.1		c.-972G>A		splice_region	Exon 1 of 13	NP_001394236.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.48G>A	p.Lys16Lys	splice_region synonymous	Exon 1 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.-838+17G>A		intron	N/A	ENSP00000454703.2	H3BN63
	PALB2	ENST00000697379.2		c.-98G>A		splice_region	Exon 1 of 14	ENSP00000513287.2	A0AA52I2C1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Familial cancer of breast (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Benign	0.93
PhyloP100		2.4
PromoterAI		-0.22	Neutral
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
Splicevardb		3.0
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: -9
DS_DL_spliceai		0.94		Position offset: 0

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

Other links and lift over

dbSNP: rs587776405; hg19: chr16-23652431;