rs774949203

Variant names:

• chr16-23637964-A-T
• rs774949203
• NM_024675.4:c.109-12T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP3 PP5

The NM_024675.4(PALB2):​c.109-12T>A variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000685846: An RNA study has shown that this variant creates a cryptic splice acceptor site in intron 2, resulting in the retention of intronic sequence (c.108_109insTCTCCTCTAG) and a frameshift in the open reading frame (PMID:27616075)." 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 intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 5.16
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000685846: An RNA study has shown that this variant creates a cryptic splice acceptor site in intron 2, resulting in the retention of intronic sequence (c.108_109insTCTCCTCTAG) and a frameshift in the open reading frame (PMID: 27616075).; SCV002734246: RT-PCR showed an insertion of 10 base pairs resulting in a frameshift protein (Kraus C et al. Int J Cancer, 2017 Jan;140:95-102).; SCV000934149: Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 21618343; Invitae).
• 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 16-23637964-A-T is Pathogenic according to our data. Variant chr16-23637964-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 490064.

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.109-12T>A		intron	N/A	NP_078951.2
	PALB2	NM_001407296.1		c.49-12T>A		intron	N/A	NP_001394225.1
	PALB2	NM_001407297.1		c.109-12T>A		intron	N/A	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.109-12T>A		intron	N/A	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.-777-12T>A		intron	N/A	ENSP00000454703.2	H3BN63
	PALB2	ENST00000697376.1		c.-789T>A		5_prime_UTR	Exon 4 of 13	ENSP00000513285.1	A0A8V8TMK8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251448 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	PALB2-related cancer predisposition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.67
PhyloP100		5.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.74		Position offset: -2
DS_AL_spliceai		0.98		Position offset: -12

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs774949203;

hg19: chr16-23649285;