16-23635320-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_ModerateBP6

The NM_024675.4(PALB2):c.1226A>G(p.Tyr409Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,786 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y409D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 5.44

Publications

5 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
Fanconi anemia complementation group N
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 3
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial ovarian cancer
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.843

BP6

Variant 16-23635320-T-C is Benign according to our data. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525. Variant chr16-23635320-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241525.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.1226A>G	p.Tyr409Cys	missense_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 link	c.1226A>G	p.Tyr409Cys	missense_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250868

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112000

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:3

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 409 of the PALB2 protein (p.Tyr409Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 33811135, 35264596, 35534704). ClinVar contains an entry for this variant (Variation ID: 241525). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 31636395, 33811135). 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. -

Nov 22, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PM2 moderate -

Mar 29, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Dec 17, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y409C variant (also known as c.1226A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 1226. The tyrosine at codon 409 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was seen in 1/7840 breast cancer patients and 1/7928 controls in the South East Asian population (Ng PS et al. J Med Genet, 2022 May;59:481-491). This alteration was found to be functional in a 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided

Uncertain:1

Sep 05, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer

Benign:1

Jan 23, 2024

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

5.4

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-7.0

D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.83

MutPred

0.64

.;Gain of sheet (P = 0.0827);

MVP

0.83

MPC

0.38

ClinPred

0.99

GERP RS

5.7

Varity_R

0.66

gMVP

0.71

Mutation Taster

=67/33

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over