Variant rs587782680 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 16-23630101-TG-T is Pathogenic according to our data. Variant chr16-23630101-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 142733.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.2052delC	p.Arg686fs	frameshift_variant	5/13	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.2052delC	p.Arg686fs	frameshift_variant	5/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152184

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

2

AN:

251460

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135906

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

21

AN:

1461886

Hom.:

0

Cov.:

32

AF XY:

0.0000179

AC XY:

13

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

4

AN:

152184

Hom.:

0

Cov.:

32

AF XY:

0.0000403

AC XY:

3

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Arg686Glyfs*23) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs587782680, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with prostate cancer and breast cancer (PMID: 25794774, 26681312, 27433846, 28194609). ClinVar contains an entry for this variant (Variation ID: 142733). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 12, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 25794774, 34113003, 28194609, 35750695); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26681312, 27433846, 28194609, 28152038, 28779002, 29625052, 32885271, 31447099, 31841383, 33646313, 25099575, 26689913, 24136930, 17200668, 33471991, 29922827, 35750695, 34113003, 33804961, 34326862, 36451132, 34887416, 25794774) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 29, 2017	- -

Malignant tumor of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2021	Variant summary: PALB2 c.2052delC (p.Arg686GlyfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251460 control chromosomes. c.2052delC has been widely reported in the literature in three affected cases of a family with breast cancer in which two unaffected obligate carrier individuals were also identified (Snyder_2015); lobular breast cancer (example, Snyder_2015, Susswein_2016), unspecified breast cancer (example, Lerner-Ellis_2017, Yang_2020), prostate cancer (example, Pritchard_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PALB2 p.Arg686GlyfsX23 variant was identified in 1 of 180 proband chromosomes (frequency: 0.006) from individuals or families with BRCA1/2 negative breast cancer (Snyder_2015_ 25794774). The proband in this study of multiplex breast cancer families, had 2 cousins with breast cancer who were carriers of the variant, a maternal grandmother who died of breast cancer at 54, and a mother and aunt who are obligate carriers of the variant but did not develop breast cancer. The variant was also identified in dbSNP (ID: rs587782680) â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, ClinVar (classified pathogenic by Ambry Genetics and GeneDx), Clinvitae (2x), and was not identified in Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2052del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 686 and leads to a premature stop codon 23 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in hereditary breast cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2024	The c.2052delC pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2052, causing a translational frameshift with a predicted alternate stop codon (p.R686Gfs*23). This alteration has been identified in multiple families with breast cancer (Snyder C et al. Breast Cancer Res. Treat. 2015 Apr;150:637-41; Susswein LR et al. Genet. Med. 2016 08;18(8):823-32; Lerner-Ellis J et al. Breast Cancer Res. Treat. 2017 04;162(3):591-596; Dorling et al. N Engl J Med. 2021 02;384:428-439) and one individual with metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375(5):443-53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 2023	This variant deletes 1 nucleotide in exon 5 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with breast cancer (PMID: 25794774, 28194609, 28779002, 31841383, 34113003) and in a breast cancer case-control meta-analysis in 6/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010946). This variant also has been reported in an individual affected with prostate cancer (PMID: 27433846). This variant has been identified in 2/251460 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 Pathogenic. -

PALB2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2024

The PALB2 c.2052delC variant is predicted to result in a frameshift and premature protein termination (p.Arg686Glyfs*23). This variant has been reported in individuals with breast cancer (Supplemental Data 2, Lu et al. 2015. PubMed ID: 26689913; Supplemental Table S1, Susswein et al. 2015. PubMed ID: 26681312) and prostate cancer (Supplementary Table S2, Pritchard et al. 2016. PubMed ID: 27433846). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as Pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142733/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

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SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

rs587782680

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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