16-23621402-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_024675.4(PALB2):c.3073G>A(p.Ala1025Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. A1025V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 3.20

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35200197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3073G>A	p.Ala1025Thr	missense_variant	10/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3073G>A	p.Ala1025Thr	missense_variant	10/13	1	NM_024675.4	P1
	ENST00000561764.1	n.420-2498C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251444 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135898

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461782 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 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: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 06, 2023	The p.A1025T variant (also known as c.3073G>A), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3073. The alanine at codon 1025 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in breast cancer cohorts (Hellebrand H et al. Hum. Mutat. 2011 Jun;32(6):E2176-88; Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). This alteration was also detected in a female diagnosed with MMR-proficient sigmoid colon cancer at age 46 years (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This alteration was found to be functionally normal in a homology-directed DNA repair (HDR) assay. (Wiltshire T et al. Genet. Med. 2020 03;22:622-632). Further, in a PARP inhibitor sensitivity assay, this alteration was found to be functionally normal (Rodrigue A et al. Nucleic Acids Res. 2019 11;47(20):10662-10677). This amino acid position is well 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	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2024	This missense variant replaces alanine with threonine at codon 1025 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies reported that this variant protein does not significantly impact PALB2 function in a homology-directed repair assays (PMID: 31636395, 33964450) and in a BRCA2 binding assay (PMID: 31586400). This variant has been reported in at least four individuals affected with breast cancer (PMID: 21618343, 29522266, 33471991, 33980423; Leiden Open Variation Database DB-ID PALB2_010680) and an individual affected with colorectal cancer (PMID: 27978560). This variant has been identified in 2/251444 chromosomes 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. -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1025 of the PALB2 protein (p.Ala1025Thr). This variant is present in population databases (rs746872839, gnomAD 0.003%). This missense change has been observed in individual(s) with breast or colon cancer (PMID: 21618343, 27978560). ClinVar contains an entry for this variant (Variation ID: 217917). 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%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400, 31636395, 33964450). 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	research	Centro Diagnostico Italiano	Apr 21, 2015	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 14, 2020

Variant summary: PALB2 c.3073G>A (p.Ala1025Thr) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3073G>A has been reported in the literature in individuals affected with breast cancer and colorectal cancer (e.g. Hellebrand_2011, Hauke_2018, Pearlman_2016). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Experimental evidence evaluating an impact on protein function demonstrated the variant to confer similar levels of activity to wild-type controls in different functional assays (Rodrigue_2019, Wiltshire_2019). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical importance becomes available. -

Fanconi anemia complementation group N Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 06, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or colorectal cancer (Hellebrand et al., 2011; Pearlman et al., 2017; Hauke et al., 2018); This variant is associated with the following publications: (PMID: 21618343, 22331464, 19609323, 20871615, 23684799, 29522266, 27978560, 27930734, 31636395, 31586400, 33964450, 31159747, 24485656) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D;D
Sift	Benign	0.047	D;D
Sift4G	Benign	0.078	T;T
Polyphen		0.94	.;P
Vest4		0.36
MVP		0.45
MPC		0.16
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.46
gMVP		0.49

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: rs746872839; hg19: chr16-23632723;