Variant rs730881878 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024675.4(PALB2):c.3235G>T(p.Ala1079Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A1079V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:9

Conservation

PhyloP100: 1.70

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22105038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.3235G>T	p.Ala1079Ser	missense_variant	12/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.3235G>T	p.Ala1079Ser	missense_variant	12/13	1	NM_024675.4	ENSP00000261584	P1
	ENST00000561764.1 linkuse as main transcript	n.185+596C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727236

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 18, 2022	The p.A1079S variant (also known as c.3235G>T), located in coding exon 12 of the PALB2 gene, results from a G to T substitution at nucleotide position 3235. The alanine at codon 1079 is replaced by serine, an amino acid with similar properties. This alteration was reported in a 7 month old patient presenting with isolated myelomonocytic sarcoma (Beer A et al. Mol Genet Genomic Med 2021 09;9(9):e1746). This alteration was also reported in 1/835 familial breast cancer cases and in 0/662 controls in one study (Damiola F et al. Breast Cancer Res. Treat. 2015 Dec;154:463-71) as well as in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). 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	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	This missense variant replaces alanine with serine at codon 1079 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, controlled functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26564480, 28779002) and ovarian cancer (PMID: 32546565). This variant has been observed in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma, as well as in his father unaffected with cancer (PMID: 34382369). In a large breast cancer case-control study, this variant has been observed in 6/60466 cases and 1/53461 unaffected individuals with OR=5.305 (95%CI 0.639 to 44.07) and p-value=0.13 (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010612). This variant has not been identified 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. -
Likely pathogenic, no assertion criteria provided	research	Hauer Lab, Department Of Pediatric Oncology, Technical University Munich	-	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 15, 2022	BP4, PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	Observed in individuals with breast cancer and also in unaffected controls (Damiola et al., 2015; Decker et al., 2017; Dorling et al., 2021); Observed in a child with myeloid sarcoma, and a fibroblast sample from this patient demonstrated increased sensitivity to radiation and DNA damaging agents (Beer et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 24485656, 19609323, 20871615, 33471991, 26564480, 34382369) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 16, 2020	- -

Familial cancer of breast

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1079 of the PALB2 protein (p.Ala1079Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or myelosarcoma (PMID: 26564480, 34382369). This missense change has been observed to co-occur in individuals with a different variant in PALB2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 182756). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 26, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 27, 2023

Variant summary: PALB2 c.3235G>T (p.Ala1079Ser) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3235G>T has been reported in the literature in individuals affected with Breast Cancer (e.g. Damiola_2015, Dorling_2021) and acute myelogenous leukaemia (Beer_2021) without evidence for causality, and also in unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all six classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

T;T

Eigen

Benign

-0.058

Eigen_PC

Benign

0.036

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L

MutationTaster

Benign

0.97

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.039

Sift

Benign

0.16

T;T

Sift4G

Benign

0.082

T;T

Polyphen

0.68

.;P

Vest4

0.35

MutPred

0.20

.;Gain of disorder (P = 0.0239);

MVP

0.40

MPC

0.14

ClinPred

0.62

GERP RS

4.2

Varity_R

0.047

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over