Variant 16-23634893-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024675.4(PALB2):c.1653T>A(p.Tyr551Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y551Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PALB2
NM_024675.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: -0.0660

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-23634893-A-T is Pathogenic according to our data. Variant chr16-23634893-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23634893-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.1653T>A	p.Tyr551Ter	stop_gained	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.1653T>A	p.Tyr551Ter	stop_gained	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727186

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter, LOVD-team, but with Curator vacancy, Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2022	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Jones et al., 2009; Casadei et al., 2011; Blanco et al., 2013; Hu et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25583207, 27829436, 31446535, 19264984, 25525159, 21285249, 24141787, 23038782, 20871615, 24870022, 23935381, 21165770, 23935836, 31589614, 29922827, 17200672, 33471991, 31636395, 31757951) -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 2021	The p.Y551* pathogenic mutation (also known as c.1653T>A), located in coding exon 4 of the PALB2 gene, results from a T to A substitution at nucleotide position 1653. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. In one study, this mutation was found to be functionally abnormal in both a homology-directed DNA repair (HDR) assay and a PARP inhibitor sensitivity assay (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This alteration was also found to be functionally abnormal in another HDR assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). This mutation has previously been reported in multiple individuals with personal history of breast cancer and family history of breast and/or pancreatic cancer (Casadei S et al. Cancer Res. 2011 Mar; 71(6):2222-9; Blanco A et al. PLoS ONE 2013; 8(7):e67538; Cerretini R et al. Breast Cancer Res Treat, 2019 Dec;178:629-636) and in trans with a partial PALB2 gene deletion in an individual with Fanconi anemia (Xia B et al Nat. Genet. 2007 Feb;39(2):159-61). 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	Dec 22, 2022	This variant changes 1 nucleotide in exon 4 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A function study has reported that this truncated variant protein disrupted PALB2 function in a homology-directed DNA repair assay (PMID: PMID: 31757951). This variant has been observed in six individuals affected with breast cancer (PMID: 21285249, 23935836, 31446535), one of whom was affected with early-onset, triple-negative breast cancer with family history of breast and pancreatic cancer (PMID: 23935836) and three others had family history of breast cancer (PMID: 31446535). This variant has been observed in compound heterozygous state with the deletion of PALB2 exons 1-10 in an individual affected with Fanconi anemia (PMID: 17200672, 17924555). Fibroblasts from this individual lacked the full-length PALB2 protein and exhibited hypersensitivity and loss of DNA damage responses after mitomycin C treatment (PMID: 17200672). This variant has not been identified 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	May 12, 2023	Data included in classification: PVS1_vstr: Truncating variant predicted to undergo NMD PM5_sup: Truncating variant with premature stop codon upstream of p.Tyr1183 PM2_sup: Absent from gnomAD PM3_mod: Xia et al 2007, confirmed in trans in patient with Fanconi Anaemia (2/3 clinical features) Data not included in classification: 2 breast cancer cases and 0 controls (Casadei et al., 2011; PMID: 21285249) 2 bilateral breast cancer patients in Argentina (Cerretini et al., 2019; PMID 31446535) 1 family in Spain, only proband confirmed to carry the variant (Blanco et al., 2014; PMID: 23935836) Evidence of loss of function from Boonen et al, 2019 HDR assay and PARP sensitivity assays -

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 11, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	This sequence change creates a premature translational stop signal (p.Tyr551*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and/or Fanconi anemia (PMID: 17200672, 21285249, 23935836). ClinVar contains an entry for this variant (Variation ID: 1243). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 11, 2023	- -

Fanconi anemia complementation group N

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

0.98

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.074

MutationTaster

Benign

1.0

Vest4

0.85

GERP RS

-0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over