Submissions for variant NM_024675.4(PALB2):c.2067G>A (p.Ser689=)

gnomAD frequency: 0.00004  dbSNP: rs371149159

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165391	SCV000216118	likely benign	Hereditary cancer-predisposing syndrome	2014-08-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197495	SCV000252858	benign	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000197495	SCV000268045	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
GeneDx	RCV000420216	SCV000518126	likely benign	not specified	2017-06-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000165391	SCV000685915	likely benign	Hereditary cancer-predisposing syndrome	2016-10-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000197495	SCV000785070	likely benign	Familial cancer of breast	2017-04-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000420216	SCV000919943	benign	not specified	2018-04-23	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2067G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 3.2e-05 in 246256 control chromosomes (gnomAD). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.2067G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Phuah_2013, Thompson_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV001119747	SCV001278186	uncertain significance	Fanconi anemia complementation group N	2017-09-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284030	SCV001469591	likely benign	not provided	2023-06-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000420216	SCV002068911	likely benign	not specified	2021-07-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165391	SCV002530665	likely benign	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000197495	SCV004019128	benign	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
CeGaT Center for Human Genetics Tuebingen	RCV001284030	SCV004033464	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BP7
Leiden Open Variation Database	RCV000197495	SCV001193180	likely benign	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356268	SCV001551388	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The PALB2 p.Ser689= variant was identified in 14 of 16340 proband chromosomes (frequency: 0.0009) from individuals or families with breast cancer and was present in 36 of 22482 control chromosomes (frequency: 0.002) from healthy individuals (Momozawa 2018, Phuah 2013, Thompson 2015). The variant was also identified in dbSNP (ID: rs371149159) as "With Likely benign, other allele", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, GeneDx, and three other submitters), and in LOVD 3.0 (4X). The variant was identified in control databases in 8 of 246256 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111712 chromosomes (freq: 0.000009), East Asian in 6 of 17248 chromosomes (freq: 0.0004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, and Finnish, populations. The p.Ser689= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004535112	SCV004715518	likely benign	PALB2-related disorder	2022-12-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).