chr16-23635324-A-G

Position:

• chr16-23635324-A-G

Variant summary

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

The NM_024675.4(PALB2):​c.1222T>C​(p.Tyr408His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,780 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 6.34

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 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, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1222T>C	p.Tyr408His	missense_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1222T>C	p.Tyr408His	missense_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461780 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727190

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PALB2 p.Tyr408His variant was was identified in 1 of 188 proband chromosomes (frequency: 0.005) from BRCA1/2-negative individuals or families with a personal and/or family history of pancreatic cancer (Hofstatter 2011). The variant was not identified in dbSNP, Cosmic, MutDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium control databases (August 8th 2016). The variant was identified in ClinVar (classified as uncertain significance by PALB2 database) and LOVD 3.0 database (1x). The p.Tyr408 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2020	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: homology directed repair activity, cisplatin sensitivity, PARP inhibitor sensitivity, and ChAM-mediated chromatin localization all comparable to wild-type (Bleuyard 2017, Boonen 2019, Wiltshire 2019); Observed in an individual with a personal history of breast cancer in published literature (Hofstatter 2011); This variant is associated with the following publications: (PMID: 21365267, 31757951, 29387807, 31636395) -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 20, 2020	PALB2 c.1222T>C has been reported in an individual with a personal history of breast cancer. It is located within the chromatin association motif (ChAM). This variant is absent from a large population dataset and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the tyrosine residue at this position is highly evolutionarily conserved across all species assessed. We consider the clinical significance of c.1222T>C to be uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2023	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 408 of the PALB2 protein (p.Tyr408His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and PALB2-related conditions (PMID: 21365267, 32522261). ClinVar contains an entry for this variant (Variation ID: 126594). 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. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 29387807, 31636395, 31757951). 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. -

Pancreatic cancer, susceptibility to, 3 Uncertain:1

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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2023

The p.Y408H variant (also known as c.1222T>C), located in coding exon 4 of the PALB2 gene, results from a T to C substitution at nucleotide position 1222. The tyrosine at codon 408 is replaced by histidine, an amino acid with similar properties. This alteration has been detected in multiple hereditary breast/ovarian cancer (HBOC) cohorts (Hofstatter EW et al. Fam Cancer, 2011 Jun;10:225-31; Velázquez C et al. J Transl Med, 2020 Jun;18:232; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Gonzalez A et al. Breast Cancer Res Treat, 2022 Jul;194:403-412). This alteration was found to be functionally normal in a homology-directed DNA repair (HDR) assay, a RAD51 foci assay, and in a PARP inhibitor sensitivity assay (Boonen RACM et al. Nat Commun, 2019 Nov;10:5296). This alteration was found to be functionally normal in another homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 Mar;22:622-632). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.2	.;M
MutationTaster	Benign	0.83	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.81
MutPred		0.61		.;Loss of sheet (P = 0.0181);
MVP		0.82
MPC		0.38
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.70
gMVP		0.69

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: rs515726064; hg19: chr16-23646645;