16-23603456-AACTTATGAATAGTGGTATACAAATATATTTCCATCTTTTTGTCCAGCCAGCAAATGAGAGTCTGTACCCGACCATTTCACAAAAGACCAATGTTGGTCAGAGACAGGTGGGAGGAGGGCAGTACACTGACCGAGAAGTAAGTCCCAAATGGCAATTGTTCCAGAAGTCAAGATTGCTGCTGCACAGTGATCTTTCACGTCACCTTCCAGGAACCTGATAGCATACAAAGAAGATATAATTCAGATTACATATCCAAAAAACAATTAAAAAAAAAAAAAAGGTCAAAACCATGTTCCCAAAACCAGCAACAGGAACAAAAATCCCTGTAACTATGAATGCCTACATTTGTAGCCTTAGAGGTCT-A

Variant names:

• chr16-23603456-AACTTATGAATAGTGGTATACAAATATATTTCCATCTTTTTGTCCAGCCAGCAAATGAGAGTCTGTACCCGACCATTTCACAAAAGACCAATGTTGGTCAGAGACAGGTGGGAGGAGGGCAGTACACTGACCGAGAAGTAAGTCCCAAATGGCAATTGTTCCAGAAGTCAAGATTGCTGCTGCACAGTGATCTTTCACGTCACCTTCCAGGAACCTGATAGCATACAAAGAAGATATAATTCAGATTACATATCCAAAAAACAATTAAAAAAAAAAAAAAGGTCAAAACCATGTTCCCAAAACCAGCAACAGGAACAAAAATCCCTGTAACTATGAATGCCTACATTTGTAGCCTTAGAGGTCT-A
• rs2142250624
• NM_024675.4:c.3351-150_*2del

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4 PP5

The NM_024675.4(PALB2):​c.3351-150_*2del​(p.Arg1117_Ter1187delins???) variant causes a stop lost, conservative inframe deletion, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R1117R) has been classified as Likely benign. The gene PALB2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 stop_lost, conservative_inframe_deletion, splice_region
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.50
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM4: Stoplost variant in NM_024675.4
• 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 VariationId is 1048983.Status of the report is no_assertion_criteria_provided, 0 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.3351-150_*2del	p.Arg1117_Ter1187delins???	stop_lost conservative_inframe_deletion splice_region	Exon 13 of 13	NP_078951.2
	PALB2	NM_024675.4	MANE Select	c.3351-150_*2del		splice_acceptor splice_region 3_prime_UTR intron	Exon 13 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.3291-150_*2del	p.Arg1097_Ter1167delins???	stop_lost conservative_inframe_deletion splice_region	Exon 12 of 12	NP_001394225.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3351-150_*2del	p.Arg1117_Ter1187delins???	stop_lost conservative_inframe_deletion splice_region	Exon 13 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.2466-150_*2del	p.Arg822_Ter892delins???	stop_lost conservative_inframe_deletion splice_region	Exon 13 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3351-150_*2del		splice_acceptor splice_region 3_prime_UTR intron	Exon 13 of 13	ENSP00000261584.4	Q86YC2

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

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

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: rs2142250624;

hg19: chr16-23614777;