rs876660109

chr16-23621386-G-Achr16-23621386-G-Cchr16-23621386-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024675.4(PALB2):c.3089C>T(p.Thr1030Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1030A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 6.04

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3089C>T	p.Thr1030Ile	missense_variant	10/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3089C>T	p.Thr1030Ile	missense_variant	10/13	1	NM_024675.4	P1
	ENST00000561764.1	n.420-2514G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.3089C>T variant in PALB2 is a missense variant predicted to cause a substitution of threonine for isoleucine at amino acid 1030 (p.Thr1030Ile). This variant has been observed with another variant in PALB2 that is tentatively classified as likely pathogenic by HBOP VCEP in an individual without Fanconi Anemia (Ambry Genetics). The phase of the variants was not determined. This variant has been tested in multiple protein assays (PMID 33964450, 31636395, 31757951, 31586400); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. This variant is absent from gnomAD v2.1.1. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BS2_supporting, PM2_supporting, BP1) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 28, 2019	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. This variant has been reported to have conflicting or insufficient data to determine the effect on PALB2 protein function (PMID: 24141787). This variant has been observed in an individual affected with breast cancer (PMID: 21618343). ClinVar contains an entry for this variant (Variation ID: 232977). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 1030 of the PALB2 protein (p.Thr1030Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2016

This variant is denoted PALB2 c.3089C>T at the cDNA level, p.Thr1030Ile (T1030I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has been observed in at least one individual with breast cancer and was associated with decreased protein stability and modestly decreased binding with RAD51C and RAD51 compared to wildtype in an in vitro assay (Park 2014). PALB2 Thr1030Ile 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, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Thr1030Ile occurs at a position that is conserved in mammals and is located within the WD4 domain as well as the regions required for interaction with RAD51, BRCA2, and POLH and for POLH DNA synthesis stimulation (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. However, in general, missense PALB2 variants are not expected to be disease causing (Tischkowitz 2012). Based on currently available evidence, it is unclear whether PALB2 Thr1030Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2018

The p.T1030I variant (also known as c.3089C>T), located in coding exon 10 of the PALB2 gene, results from a C to T substitution at nucleotide position 3089. The threonine at codon 1030 is replaced by isoleucine, an amino acid with similar properties. This variant was identified in a series of >800 familial breast cancer cases in Germany (Hellebrand H et al, Hum. Mutat. 2011 Jun; 32(6):E2176-88). Functional analyses of the p.T1030I allele have shown reductions in protein stability and binding efficiency to RAD51C and RAD1, but intact BRCA2 interaction (Park JY et al, Oncogene 2014 Oct; 33(40):4803-12). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Service de Génétique Médicale, Institut Central des Hôpitaux

Jul 17, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	D;D
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.87
MutPred		0.51		.;Loss of sheet (P = 0.1158);
MVP		0.77
MPC		0.36
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876660109; hg19: chr16-23632707;