rs180177111

Positions:

• chr16-23629831-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.2323C>T​(p.Gln775Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q775Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PALB2 NM_024675.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 2.27

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]

ACMG classification

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 16-23629831-G-A is Pathogenic according to our data. Variant chr16-23629831-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 126646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629831-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2323C>T	p.Gln775Ter	stop_gained	5/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2323C>T	p.Gln775Ter	stop_gained	5/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251456 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000873 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2021	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 24, 2023	This sequence change creates a premature translational stop signal (p.Gln775*) 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 (rs180177111, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 18053174, 19863560, 23302520, 23341105). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126646). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 22, 2022	This variant changes 1 nucleotide in exon 5 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in at least 20 individuals and families affected with breast, ovarian and pancreatic cancer with family history of multiple cancer types (PMID 18053174, 19863560, 23341105, 23302520, 28825143, 30322717, 30720863, 31841383, 33471991; Leiden Open Variation Database DB-ID PALB2_010100). This variant has been identified in 1/251456 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2023	The p.Q775* pathogenic mutation (also known as c.2323C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 2323. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This alteration has been identified in several breast and/or ovarian cancer families and established as a founder mutation of French-Canadian origin (Foulkes WD et al. Breast Cancer Res. 2007;9(6):R83; Tischkowitz M et al. BMC Med Genet. 2013 Jan;14:5; Wark L et al. Genes Chromosomes Cancer 2013 May;52(5):480-94; Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488). This alteration has also been detected in a cohort of Chinese breast cancer patients (Zhang K et al. Breast Cancer Res. Treat., 2017 Dec;166:865-873). 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. -

Malignant tumor of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 18, 2022	Variant summary: PALB2 c.2323C>T (p.Gln775X) 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 4e-06 in 251456 control chromosomes (gnomAD). c.2323C>T has been reported in the literature in multiple individuals affected with Breast Cancer (e.g. Tischkowitz_2013, Yang_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Pauty_2017). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. 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.Gln775* variant was identified in 6 of 1936 proband chromosomes (frequency: 0.003) from individuals or families with breast and or ovarian cancer and was not identified in 24880 chromosomes from healthy controls (Foulkes 2007, Tischkowitz 2013, Catucci 2016). The variant was also identified in dbSNP (ID: rs180177111) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and three other submitters), LOVD 3.0 (7x), and in Zhejiang University Database (1x). The variant was not identified in the Cosmic database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln775* variant leads to a premature stop codon at position 775, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2 assosiated cancers and is the type of variant expected to cause the disorder. The variant has been found to recur in French Canadian HBC families and breast cancer cases and is considered a founder mutation in the French Canadian population (Arcand 2015). In a structure–function analysis of PALB2 the variant was able to bind the same DNA substrates as wild-type PALB2 (wt) but with some differences in affinity; it displayed reduced affinity for the D-loop and ability to form foci in the nucleus (Pauty 2017). In addition, mean fluorescent intensity was significantly increased and reduced telomeric signals were observed in cells carrying the PALB2 c.2323C>T variant which were generated from patient-derived cell lines (Wark 2013). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

not provided Pathogenic:1

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); This variant is associated with the following publications: (PMID: 25525159, 30322717, 32885271, 18053174, 28158555, 19863560, 24485656, 31841383, 28825143, 28888541, 31784482, 29922827, 34861889, 26137147, 32339256, 23341105, 25099575, 23302520, 21947752, 30720863, 32300229, 27624329) -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

BRCAlab, Lund University

Aug 26, 2022

- -

Breast cancer, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.34	N
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs180177111; hg19: chr16-23641152;