rs180177123

Positions:

• chr16-23626252-G-A
• chr16-23626252-G-C
• chr16-23626252-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024675.4(PALB2):​c.2732C>T​(p.Thr911Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 6.71

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2732C>T	p.Thr911Ile	missense_variant	7/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2732C>T	p.Thr911Ile	missense_variant	7/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000325 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 911 of the PALB2 protein (p.Thr911Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer, prostate cancer, colorectal cancer, and breast cancer (PMID: 19635604, 26898890; Invitae). This missense change has been observed to co-occur in individuals with a different variant in PALB2 that has been determined to be pathogenic (PMID: 19635604, 26898890; Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 126676). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2024	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 11, 2016	Variant summary: The PALB2 c.2732C>T (p.Thr911Ile) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). PALB2 Thr911Ile alters an amino acid that is moderately conserved across species and is located in the WD40 repeat domain, the region responsible for interaction with RAD51, BRCA2, and POLH (Uniprot). This variant is absent in 121368 control chromosomes, but has been reported in one young-onset pancreas cancer case with no family history (Tischkowitz_Gastroenterology_2009) and one HBOC patient (Caminsky_ATM_Hum Mut_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS. Because of limited clinical information and lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2014	This variant is denoted PALB2 c.2732C>T at the cDNA level, p.Thr911Ile (T911I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has been previously reported in a patient with early onset pancreatic cancer with no family history (Tischkowitz 2009). PALB2 Thr911Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Thr911Ile occurs at a position that is moderately conserved across species and is located in the WD1 repeat domain, the region responsible for interaction with RAD51, BRCA2 and POLH (Uniprot). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PALB2 Thr911Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 09, 2022	The p.T911I variant (also known as c.2732C>T), located in coding exon 7 of the PALB2 gene, results from a C to T substitution at nucleotide position 2732. The threonine at codon 911 is replaced by isoleucine, an amino acid with similar properties. This variant was observed in 1/287 patients with hereditary breast and/or ovarian cancer; this patient was diagnosed with breast cancer at age 56 and had a family history of breast cancer (Caminsky NG et al. Hum. Mutat., 2016 07;37:640-52). In another study, this variant was seen in 1/254 cases with pancreatic adenocarcinoma; this individual was diagnosed with young-onset pancreas cancer and did not have a family history of cancer (Tischkowitz MD et al. Gastroenterology, 2009 Sep;137:1183-6). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 28, 2020	This missense variant replaces threonine with isoleucine at codon 911 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer with family history of the disease (PMID: 26898890) and an individual affected with pancreatic cancer (PMID: 19635604). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.52
MVP		0.68
MPC		0.33
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.60
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs180177123; hg19: chr16-23637573;