16-23614011-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_024675.4(PALB2):c.3194C>G(p.Ser1065Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,400 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1065F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.14

Publications

2 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:

ENSG00000261723 (HGNC:58305):

ENSG00000261723 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 30 uncertain in NM_024675.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.779

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PALB2	NM_024675.4	MANE Select	c.3194C>G	p.Ser1065Cys	missense	Exon 11 of 13	NP_078951.2
PALB2	NM_001407296.1		c.3134C>G	p.Ser1045Cys	missense	Exon 10 of 12	NP_001394225.1
PALB2	NM_001407297.1		c.3122C>G	p.Ser1041Cys	missense	Exon 10 of 12	NP_001394226.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3194C>G	p.Ser1065Cys	missense	Exon 11 of 13	ENSP00000261584.4
PALB2	ENST00000568219.5	TSL:1	c.2309C>G	p.Ser770Cys	missense	Exon 11 of 13	ENSP00000454703.2
PALB2	ENST00000561514.3	TSL:5	c.3200C>G	p.Ser1067Cys	missense	Exon 11 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459228

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726112

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109728

Other (OTH)

AF:

0.00

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Nov 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S1065C variant (also known as c.3194C>G), located in coding exon 11 of the PALB2 gene, results from a C to G substitution at nucleotide position 3194. The serine at codon 1065 is replaced by cysteine, an amino acid with dissimilar properties. This variant has been identified in breast cancer cohorts (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). Internal structural analysis indicates this variant in structurally disruptive (Oliver AW et al 2009 EMBO Rep. 2009 Sep; 10(9): 990–996; Siaud N et al, PLoS Genet. 2011 Dec; 7(12):e1002409; Ambry internal data). This amino acid position is well 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.

Jan 23, 2020

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with cysteine at codon 1065 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31404 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.

Jul 02, 2018

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial cancer of breast

Uncertain:2

Mar 22, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1065 of the PALB2 protein (p.Ser1065Cys). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 480249). 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%. 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.0

PhyloP100

6.1

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.37

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.72

MutPred

0.45

Loss of ubiquitination at K1062 (P = 0.0877)

MVP

0.82

MPC

0.34

ClinPred

0.98

GERP RS

6.1

Varity_R

0.60

gMVP

0.67

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over